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CHAPTER
Epilepsy
Michael A. Rogawski
1. lntraduction
Epilepsy, a condition of recurrent, paroxysmal seizures, is amajor, worldwide, health problem. The epileptic seizure representsan abnormal synchronized discharge among a large population of
central neurons. Although the cause of this synchronized activity is
largely a mystery, the occurrence of seizures in a n epileptic patientcan be diminished or eliminated by drugs that target the basic excit-
ability mechanisms of neurons. Most presently used antiepilepticmedications were deveIoped by empirical drug screening or seren-
dipity. However, in the past several decades, as understanding of fhe
functional activity of brain circuits has increased, there has been an
intense effortto develop new antiepileptic medications on a rationalbasis.
Although progress has been measured, some rationally devel-oped antiepileptic drugs are now entering the market.The focus of attention for the rational design of antiepileptic
drugs has been to target, either directly or indirectly, ion-conductingchannels--the fundamental mediators of electrical excitability in
neurons. There are two major classesofneuronal ion channels: volt-age-dependent channels that shape the subthreshold electrical
behavior of the neuron, allow it to fire action potentials, and regulate
Neurotherapeutics: Emerging StrategiesEds.: L. Pullan and 4 . Patel Hurnana Press Inc., Totowa, NJ
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194 Xogawski
its responsiveness EO synaptic signals; and neurotransmitter-rep-
lated channels that mediate the synaptic signals,Each of these two
classes of channel participates in the electrical events o f he seizure.
Voltage-dependentchannels contribute to the paroxysmal depolariz-ing shift, the single ceII correlate of the interictal (between seizure)
network discharge. Voltage-dependent channels also mediate actionpotentials that allow transmission of the seizure discharge along
axons to neighboring cells and distant brain sites. The neurotransmit-ter-regulated channels allow the abnormal discharge to propagatebetween neurons within the neuronal aggregate and alsoparticipate
in the paroxysmal depolalizing shift. The voltage-dependent ion
channels include channels selective for Na+ and K+, that shape thesubthreshold behavior of neurons and mediate action potentials aswell as channels selective fox Ca2+hat appear to play a critical,role
in absence seizures (see Section 7.).Neurotransmitter receptor chan-
nels include the fast-acting channels for the major excitatory and
inhibitory neurotransmitters, glutamate and GABA, as well as far
regionally specific transmitters such as monoamines (catechola-mines, serotonin, and histamine) and neuropeptides. In addition to
rapid actions, the transmitters canmediate slower modulatory" sig-
nals, where the receptor is coupled to an ion channel via G-proteinsor other second messengers.
In principle, it may be possible to prevent the occurrence of
seizures by targeting any one or a combination of these systems, sothat there is an enormous variety of possible anticonvulsant strate-gies. The ultimate goal is, of course, to prevent the generation orpropagation of seizure discharges without interfering with the nor-
mal functioning of the nervous system. (An additional and perhaps
more satisfying goal is to prevent the development of epilepsy; thereare some important leads along these lints as discussed in Section
3.1.)Given the critical role of the neuronal excitability mechanismsmediating seizures for normalbrain function, it would seem improb-
able thatan anticonvulsantdrugcould be developedwhich suppressed
seizures without producing side effects. Nevertheless, several pres-ently available anticonvulsant drugs approach this goaI, indicating
that it is attainable.
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In this chapter, I consider a variety of approaches that are cur-
rently under investigation for the rational development of new anti-
epileptic drugs.The mechanisms of presently available antiepileptic
drugs has been reviewed previously (Rogawski and Porter, 1990),and are not considered in detail here.
2. Potentiationof Synaptic Inhibition
Enhancement of synaptic inhibition mediated by GABAA
receptors is an important anticonvulsant strategy. This can occur bytargeting of the GABAA receptor itself, or by enhancement of synap-tic GABA levels. Drugs that enhance GABAA receptor-mediated
inhibition show a distinctive spectrum o f activity in animal seizuremodels. Such drugs typically protect very effectively againstpentylenetetrazol seizures,but have far weaker activity in the maxi-
mal electroshock test.Despite the selectivityoftheir effects in animal
seizure models, GAB&-receptor potentiating anticonvulsants mayhave a broad spectrum of activity in human seizure disorders.However, they are generally ineffective in absence seizures. (Benzo-
diazepine receptor agonists that do have anti-absence activity are anotable exception to this rule.)
2.1. GABA, Receptors as Targetsfor Anh'epilep t ic Drugs
Presently available drugs that potentiate GABAA eceptor
responses fa11 into two broad classes: benzodiazepine-like and bar-biturate-like modulators. In addition, there are a variety of agents,including neuroactive steroids and loreclezole, hat act similarly to
barbiturates, but probably interact with distinct sites on the GABAAreceptor complex.
2.1.1. Novel Benzodiazepine Receptor Ligands
Benzodiazepine receptor agonists, such as diazepam and
lorazepam, have powerful anticonwlsant properties as a result of
their ability to enhance GABAA receptor-mediated neurotransmis-sion in the central nervous system (CNS). Although such benzodiaz-
epine agonists have an impor.tant role in the acute treatment of statusepiiepticus (continuous seizures without return to consciousness),
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196 Rogaws i
two significant limitations largely preclude their chronic use in epi-Iepsy therapy. The first limiting factor is that these benzodiazepinesproduce undesirable side effects, including sedation and muscle
relaxation,at doses comparable to those that protectagainst seizures.The second,andprobably more important,Iirnitation isthat tolerance
develops to the anticonvulsant activity ofbenzodiazepines receptoragonists with chronic use. In recent years, considerable effort has
been directed toward developing strategies for overcoming theselimitations. A variety o f benzodiazepines and nonbenzodiazepineshave been identified that interact with the benzadiazepine binding
site of the GABAn receptor complex in novel and potentially morefavorable ways. As yet, however, there is no convincing evidencethat any of these benzodiazepine receptor ligands will have practical.utility in the chronic treatment of epilepsy.
2.1.1.1. RENZODIAZEPINEECEPTOR ARTIALGONISTS.artialaganisrnatthe benzodiazepinereceptorhasbeen proposedby Haefely
(seeHaefely et al., 1990) as a promising approach to overcame the
undesirable side effects and the propensity to the development of
tolerance of full benzodiazepine agonists. Bartiat agonists have lowintsinsic efficacy and induce smaller responses than do full agonists
at the same fractional receptor occupancy. Thus, at full receptoroccupancy, partial agonists produce submaximal biologicalresponses.However, the degreeof partial agonismmay vary depending
on the subunit composition of the GAB& receptor W f l a c h et al.,1993).At anticonvulsant doses, partial benzodiazepine receptoraga-
nistsmay produce less sedation and muscle relaxation than full ago-nists, and may also exhibit less tolerance and physical dependence.
Benzodiazepine receptor partial agonists have been identified
within several structural classes, including me benzodiazepines
(bretazenil, FG 8205; Martin et al., 1988; Tricklebank et al., 1990),
P-carbolines (abecarnil,ZK 1296; tephens et al., 1990; etersen
et al., 1984),pyrozoloquinolines (CGS 9896;Bernard et al., 19851,imidazopyrimidines divaplon; Garhe r , 1988), and quinolizinones(Ro 19-8022;Jencketal.,1992).Samepartial agonist-for example,Ro 19-8022-have anticonvulsant potency and efficacy in animal
seizure models comparable to full benzodiazepine receptor agonists
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Epilepsy 197
(Jenck et al., 1992; Facklam et a]., 1992a; Jensen et al., 1984).How-ever, Ro 19-8022 has lower eficacy for sedation and muscle relax-ation, and may also have reduced physical dependence liability.
Moreover, Ro 19-8022does not exhibit proconvulsant activity (likebenzodiazepine inverse agonists); nor is an abstinence syndrome(characterized by tremors and seizures) precipitated when chroni-cally treated animals are exposed to a benzodiazepine receptorantagonist. Interestingly, in line with the efficacy of conventionaI
benzodiazepines in human absence epilepsy, Ro 19-8022 has beenreported to be effective in a rodent genetic model of absence epi-lepsy. Other benzodiazepine receptor partial agonists, including
bretazenil (Haigh and Feely, 1988; Facklam et aI., 1992a) anddivaplon (Feely et al., 1989;Deacon et al., 1991) similarly display
potent anticonvulsant activity, but less sedation and anticonvulsanttolerance than diazepam.Studies using recombinant GABAn recep-
tor subunits have demonstrated that bretazenil and divaplon possess35-58% and 2 1-28%, respectively, of the intrinsic efficacy of the
full agonist flunitrazepam (Knoflach et al., 1993;see also Facklamet al., 1992b).
How can w e understand the law propensity of benzodiazepinereceptor partial agonists to produce sedation, muscle relaxation, and
tolerance? It is now recognized that full benzodiazepine receptoragonists, such as df azepam,produce anticonvulsant effectswith low
receptor occupancy (Fig. I ) . For example, it has been estimated thatfull benzodiazepine receptor agonists protect against sound-induced
seizures in mice at occupancy levels of 2-5% and against penty-lenetetrazol seizures at occupancy levels of 25% (Braestrzlp and
Nielsen, 1986).In contrast, 70-90% occupancy is needed forprotec-tion against tonic hindlimb extension in the maximal electroshock
test (Petersen et al., 1986). Similarly, sedative effects as assessedwith various tests of motor impairment also require high levels ofoccupancy (50-76%; Petersen et al., 1986). Thus, full benzodiaz-epine receptor agonists exhibit anticonvulsant activity (against
sound-induced and pentylenetetrazol seizures) at low doses, and
sedation at higher doses. For partial agonists to elicit the sameresponse as a full agonist, higher levels of receptor occupancy are
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Xogawski
-
-
-SPONTANEOUS
ABSENCE IRAT)AUDIOGENIC
Fig. 1. The various actions of the full benzodiazepine receptor agonist
diazepam occur at different levels of receptor occupancy. Thus,partial ago-
nists may not produce behavioral effects requiring high IeveIs of occupancy,
such as impairment ofmotor function in the rotarod test. In vivo radioligandmethod for determinationof receptoroccupancy is described in Petersen et al.(1984). Audiogenic = protection against sound-induced seizures in D B N 2mice; MES =maximal electroshock test;DMCM =protection against seizures
induced by the benzodiazepine receptor inverse agonist merhyl 6,7-
dimethoxy-4-ethyl-b-carboiine-3-carboxylate. ata obtained in the mouse(except as notedlare fromBraestmpand Nielsen ( 1 986), Petersenetal. (1984) ,
Jensen et al. (19X4), nd Petersen et al. ( 1 986).
required, The requirement for higher occupancy is presumablybecause the potentiation of each GABAAreceptor is smaller and
more GABAAreceptors must be recruited to obtain an equivalentresponse. For example, in one study, 50% protection in the penty-
lenetetrazol test was reported to occurwith 37% receptor occupancyby diazepam and 84%receptor occupancy by ZK 1296, a partial
agonist (Petersen et al., 1986). For benzodiazepine agonist effects
that require a high degree of GABAAreceptor potentiation (e.g.,
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muscle relaxation, ataxia, amnesia, and respiratory depression), it
may not be possible to achieve the pharmacological effect with apartial agonist, even with full occupancy. Thus, partial agonists can
have anticonvulsant activity and yet not show adverse side effects at:
any dose.There is substantial evidence that benzodiazepine receptor
tolerance occurs as a result of a downregulation in the expression ofcertain GABAA receptor subunits, particularly the p subunit that
confersbenzodiazepine sensitivity (Zhao et a1., 1994).Nevertheless,
since the mechanism coupling chronic receptor activation tochangesin the expressfan of the y2 subunit gene is not well understood, it is
not yet possible to explain the reduced tendency ofpartial agonists to
induce tolerance. Despite the very favorable properties af benzodi-azepine receptor partial agonists, as yet there is no clinical data sup-
porting the utility of these compounds in epilepsy therapy.
Certain benzodiasepine receptor partial agonists, such asabecamil,may have a distinct spectrum of anticonvulsant activity in
comparison with conventional benzodiazepine receptor agonists suchas diazepam (Turski et al., 1990). For example, abecarnil is highly
active in a variety of chernoconvulsant models (Sersa et al., 19921,but, unlike diazepam, is inactive in the maximal electroshock test.
The differences in the spectrum of anticonvuEsant activity may relate
to the unique GABAA receptor subunit specificity of abecarnil.Recent studies with cloned GABAA receptor subunits indicate that
abecarnil can exhibit partial or fuI1 agonist properties at differentGABAA eceptor subtypes,mainly dependent on the molecular formof the a-subunit (Knoflach et al., 1993; PribiIla et al., 1993).Thus,the unique ph m ac a lo gi ca l profile of abecarnil could arisefrom ts
actions as a partial agonist at some GABAA receptors and as a fu11
agonist at others. Animals treated chronically with abe~arn i l o not
exhibit a diazepam-like withdrawal syndrome on discontinuation ofthe drug (Loscheset al., 1990;Steppuhn et al., 1993;Llischer, 1993)-
Moreover, the development of anticonvulsant tolerance to abecarnilis dependent on he model used. Indeed, in some experimental para-digms no anticonvulsant tolerance is exhibited at the same time that
to1erancedevelops to the motor impairing activityof the dmg (Loscheret al., 1991b; Serra et aI., 1994).
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200 Rogawski
2.1.1 -2.BENZODIAZEPTNEECEPTOR SUBTYPE-SELECTWEGONTSTS.
Abecamil is an exampIe ofa benzodiazepinereceptor ligand that actsas a partial agonist at some GABAA receptor subunit combinations
and not others. It therefore exhibits some subtype selectivity. Theimidazopyridines alpidem and zolpidem, in contrast, show nearIy
complete subtype selectivity. These compounds exhibit GABApotentiating activity at, for example, GABAA eceptors of composi-
tion a lBzyz , 2Ply2, lP lyz ,but not aSP2y2(Faun-Halley et al., 1993;Wafford et al., 1993; Horne et al., 1992). In binding to brain tissue,alpidernandzolpidem show selectivityfortheoli'BZ1subtype ofre ceptor (Benavides et al., 1988; Benavides etal., 1993).AIpidem has anti-
convulsant activity comparnbIe to benzodiazepines, but exhibits
much-reduced sedative and muscle relaxant activity (Garreau et al.,1992). In addition, the drug fails to induce tolerance or dependence(Perrault et al., 1993).Human trials of alpidem asan anxiolytic have
been promising,with a very favorable side-effect profile in compari-sonwith conventional benzodiazepines.Alpidem binding exhibits a
differential regional: localization in brain that correlates roughly withthe presence of al/BZt binding sites. It has been suggested that the
regional selectivityofalpidemforw /BZl bindingsites,whichisdepen-
dent on the unique subunit specificity of the drug, could account forits favorable properties (Benavides et al., 1993).On he other hand,
the possibility that alpidern is a partial agonist at certain GABAP,
receptor subtypes couldalso explain its favorable profile (Perraultetal., 19933. However, recent studies with cloned subunitshave dem-
onstrated that alpidern (Imet al., 1993) and zolpidem (Horne et al.,1992) ase full agonistsat some, if not aII,GABAA eceptorsubtypes.
2.1.2. Barbifurafe-LikeDrugs
Barbiturates have fallen out of favor as anticonvulsant agents
largely because of their propensity to cause sedation, behavioral
impairment, and deleterious effects on cognitive performance(Fawell et al., 1990).Nevertheless,barbituratesare highly effective,
broad-spectrum anticonvulsants. Barbiturate-like compounds withimproved side-effectprofiles would provide interesting candidates
for clinical development.
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Epilepsy 201
The sedative and anticonvulsant activity of barbiturates is
believed to be mainly due to their potentiationofCNS GABA-mediatedinhibition (Scholfield, 1938). This occurs by prolongation of burst
openings of singleGABARreceptorchannels (Macdonaldetal., 1989).However, effects on voltage-activated CaZ+ hannels also appear to
play a role in the sedative-hypnotic activity of the barbiturates andcould participate in their therapeutic activity as anticonvulsants
(ffrench-Mullen et al., 1993). In addition, direct activation o f the
GABAn receptor could account for the sedative-hypnotic side effectsof certain barbiturates (Rho et al., 1994b). Finally, barbituratesappear to have actions an excitatory amino acid receptors, withparticular selectivity for AMPA (a-amino-3-hydroxy -5-methy1-4-isoxazalepmpionic acid) receptors (Tavernaet al., 1994;Donevan and
Rogawski, unpublished). In line with the diversity of barbiturate cel-lular actions, there are wide differences in the pharmacologicalprop-erties of structurally similar barbiturates. Pentobarbital is a powerfulsedative-anesthetic, whereas the less sedative phenobarbital is usedmainly as an anticonvulsant.Although still incompletely understood,the basis for the reduced sedation with phenobarbital may relate torelative affinities for different target sites and also to the magnitudes
of effects produced at clinically relevant concentrations.For example,ithasbeenproposed that the stronglydepressantaction ofpentobarbita1could relate to its activity both as a GABA potentiator and a Ca2+
channel blocker. Phenobarbital, in contrast,has a higher affinity forGABAA receptors than forCa2+ hannels (ffrench-Mullenet aI., 1993).At clinically relevant concentrations, it may mainly act as a GABApotentiator, but the absolute magnitude of the potentiation may be
smaller than that produced by pentobarbital.The lack of effect on Ca2+
channels and the less robust potentiation could account for its lowertoxicity. As the concentration of phenobarbital moves into thesupratherapeutic (toxic) range, it becomes more strongly sedative,
possibly because effects on Ca2' channels become prominent. Thetypes ofCa2+ hannels relevant to the action of barbiturates have notbeen well defined. One hypothesis is that these are presynaptic chan-nels involved in the regulationofneurotransmitter release, and that the
depressant action is Iargely due to a reduction of glutamate release.
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202 Rogawski
It may be possible to obtain even greater reductions in the seda-
tive-hypnotic activity of barbiturate-like GABA modulators. Thus,the newly introduced anticonvulsant felbamate has a very favorable
side effectprofile (causing agitation and insomnia more frequentlythan sedation; Faught et al., 19931, and appears to act, in part, as a
barbiturate-like modulator of GABAA eceptors (Rho et aE., 1994~) .(Felbarnate produces certain severe idiosyncratic toxicities, unre-lated to its anticonwlsant action, that limit its clinical utility.)Felbamate is a dicarbamate structuralIy related to the sedative-anxiolytic meprobamate. Meprobamatehas also recentlybeen shown
to have barbiturate-like activity. However, it is much more potentand, unlike felbamate, can directly stimulate the opening of GABAA
receptor coupled CI- hannels in the absence sfGABA (Rhoet
al.,1994a). This latter activity could contribute to the propensity ofmeprobamate to cause greater CNS depression. In addition to its
activity as a barbiturate-Iike modulator of GABAA receptors,felbamate also can inhibit NMDA receptors as discussed in Section
3.1.5. This effect could produce behavioral activation that wouldcounterbalance the CNS depression resulting from GABA potentia-
tion. (NMDA antagonists typically have behavioral activating effects
at low doses;Willetts et al., 1990.)
It hasbeen known for over fivedecades that the steroidsproges-
terone and deoxycorticosterone acetate have anticonvulsant activity
against pentylenetetrazol seizures (Selye, 1942; Craig, 1966), In theintervening years, other structurally related steroids, including 3,20-
pregnenediones nd 3,20-pregnanediones (Craig and Deason, J968),2P-morpholino-5a,3a-pregnanoIonesHewett et al., 19641, and the
steroid anesthetic alphaxalone (Peterson, 1989), have been reportedto have similar activity. In 1984,Harrison and Simmonds made the
seminal discovery that alphaxalone could selectivelypotentiate cen-tral neuron responses to GABA (but not glycine). The 3P-hydroxy
isomerbetaxalone was inactive, indicating ahigh degree of structural
specificity. Morerecently, it has been recognized that certain endoge-
nousmetabolites of progesterone and deoxycorticosterone are also
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Epilepsy 203
highly potent modulators of the GABAn receptor (Majewska et aE.,
1986). These metabolites have anticonvulsant activity (Belelliet al.,1989, 1990;Bogskildeet al., 1988),and their anticonvulsantpoten-
cies correlate strongly with their ability to modulate GABAA eceptorcurrent (Kokate et al., 1994).Studiesusing fluctuation (noise) analy-
sis and single channel recording have demonstrated that the steroidsproduce a barbiturate-likeprolongation ofburstopeningsofGABAA
receptors (Sirnmonds, 1991;Twyrnan and Macdonald, 1992).In addi-
tion, they may causean increaseinchannel-openingfrequency,an effectnot observed with barbiturates. Like barbiturates, neuroactive steroidscan directly activate the GABAA eceptor in the absence of GABA.
Do neuroactive steroids have potential in the treatment of sei-
zure disorders? Although highly active against seizures induced by
pentylenetetrazol and other GABA receptor antagonists including
bjcuculline and picrotoxin, GABA-potentiating neuroactive steroidsare inactive in the maximal electroshock test. This contrasts with
phenobarbital which shows some activity in the maximal electroshock
test (Belelli et al., 1990).The profile of the steroids in animal seizuremodels suggests that their primargr utility may be in the treatment ofabsence epilepsy (Rogawski and Porter, 1990). Indeed, there is ananecdotal report ofthe effectiveness of deoxycorticosterone acetate
in six of eight absence seizure patients (Aird and Gordan, 1951).
The extent to which neuroactive steroids can protect against
seizures at nontoxic (nonsedating) doses is not clear. All GABA-potentiating neurosteroids cause impairment of motor performance.However, there may be differences among stmcturally similar neu-roactive steroids in relative toxicity. Progesterone and certain
pregnene and pregnane 3,20-diones exhibit a degree of separationbetween their anticonvulsant and toxic doses, but are relatively weak
anticonvulsants(Craig and Deason, 1968). However, alphaxalone, amare potent anticonvulsant, protects against seizures only at dosesthat produce neurological impairment (Peterson, 1989).In a compre-hensive study of progesterone and deoxycorticosteronemetabolites,
there was up to a several-fold separation between the protective andtoxic doses. Thus the therapeutic index (ratio of the ED50 values formotor impairment and for protection in the pentylenetetrazol seizure
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test) ranged from 1.2-3.8 (Kokate et al., 1994). However, the thera-peutic indices of a11of the steroidswere less than that of the benzo-diazepine clonazepam (8.9). Recently, steroid-like substituted
bentejindenes (tricyclic molecules containing only a portion of the
steroid A-ring) have been described which potentiate GABA
responses and may have toxicity comparable to the most favorableneurosteroids (Rodgers-Neame et a1., 1992). Further structure-activity studies may lead to the identification of steroids with
improved toxicity profiles. However, a key-but as yet unan-swered-question iswhether neurosteroids will exhibit tolerance as
do benzodiazepines. If so, like benzodiazepines, they will have lim-
ited utility in the chronic therapy of seizure. (A recent study failed to
observe any tolerance to the anticonvulsantactivity ofpregnanolonein the pentylenetetrazol test;Kokate et aI., 19956.)However,even if
tolerance does develop over time, steroidsmay stiIl be of value in theacute treatment of status epilepticus,as are benzodiazepines. In fact,the steroids appear to be highIy effective in the kainate and piIo-
carpinemodelsofstatusepilepticusin themouse(KokateandRogawski,1994;Kokate etal., 1995a). Because the solubility of steroids is poor,
selection of an appropriate vehicle or identificationo f water soluble
prodrug forms will be critical.Recently, the synthetic 3P-methyl analog of epiallopregnano-
Ione (3a-hydroxy,3P-methyl-5a-pregnan-20-one; CCD 1042) as
been demonstrated to have anticonvulsant potency that is onlyslightly weaker than its parent.However,the 3P-methylation confersgood metabolic stability and oral activity. In Phase I cIinical trials,CCD 042was well-toleratedat levels substantiallyhigherthan hoseassociated with seizure protection in animals (K. . Gee,personal
communication, 1995).
2.1.5. y-Bufyrolactones and y-Thiobutyrolactones
Anadditional seriesofGABAA receptormodulatingcompoundshas recently been described that appear to act at a site distinct f o m
benzodiazepines, barbiturates, and steroids (Holland er aI., 1993).This novel recognition site, referred to as the y-butyrolactone (GBL)
site, is the locus of action of a variety of substituted y-butyolactones
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Ep i l e p s y 205
and y-thiobutyrolactones.Certain ligands ofthe GBL site antagonize
GABAA eceptorresponse andare convulsant,whereas otherspoten-tiate GABA responses and have anticonvulsantproperties (Holland
et al., 1990). Anticonvulsant GBL site ligands, such as a-ethyl,a-methyl-thiobutyrolactone (a-EMTBL), are protective in the penty-
lenetetrazol seizure model as are other GABA-potentiating drugs.However, GBL site ligands may also be effective in the maximalelectroshock test and other seizure models (Ferrendelli et al., 1989;
Holland et al., 1992).a-EMTBL has a therapeutic index that is lowrelative to other GABA modulatinganticonvulsants,but i s similarto
valproate. Preliminary results indicate that a-EMTBL may demon-strate lesstolerancethanclanazepan,suggestingthat GBL siteligands
may be ofutiIity in chronicepiIepsytherapy (Ferrendellietal., 1993).
Loreclezole is a novel triazolederivativethat is protective againstpentylenetetrazolseizuresbut is lessactive in the maximal electroshock
test (Wauquier et al., 1990;Kulak and Sobaniec, 1994).In addition,atlow, nontoxic doses, the drug has anti-absence activity in a genetic
model of generalized absence epilepsy (Ates et al., 1992). Conse-quently, loreclezole has a profile of activity similar to that of otherbenzodiazepines. A potential benzodiazepine-Iike interaction withGABA, receptors is suggested by the observation that the anticon-
wlsant effectsofloreclezolecanbe reversed bybenzodiazepine ecep-tor inverseagonists (Vaught and Wauquier, 1991; Ashton etal., 1992).
The benmdiazepineantagonistflumazenil,however, failed toaltertheanticonvulsantactivityofloreclezole, ndicating that loreclezole is not
a benzodiazepinereceptor agonist (Wauquier etal., 1990).Moreover, onchronic (5-7 d) administration, tolerance did not develop to th e anti-
conwlsant effects of Ioreclezole as it does with benzodiazepines.LorecEezole can indeed enhance the activity of GABAA ecep-
tors, but it interacts with a novel allosteric modulatory site distinctfrom that of benzodiazepines, barbiturates, or neuroactive steroids(Wafford et al., 1994).Using native rat and cloned human GABAA
receptors, loreclezole strongly potentiated GABA-activated C1- cur-rent. However, activityof the drug did not require the presenceof the
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y-subunit and was not blocked by flumazenil, confirming that
loreclezoIe does not interact with the benzodiazepine recognitionsite. Interestingly, loreclezole had >300-fold activity an receptors
containing the P I - or p3-subunit n comparisonwith those containingthe I subunit.Usingchimeric P-subunitsand site-directed mutagen-
esis, it was demonstrated that a single amino acid, at the carboxyl-terminal end of the P-subunit putative channel-lining domain TMZ,confers sensitivity to loreclezole (Wingrove et al., 1994).The affin-
ity for GABA and benzodiazepines was unaltered by amino acidsubstitutions at this site.
Loreclezole reduced seizuse occurrences in several small clini-
cal trials and was rdatively free sf side effects (Rentmeester and
Hulsman, 19921, demonstrating the potential ofdrugs that modulateGABAAreceptors in novel ways.
2.2. Vigabatrr.'~~,GABA Transamitrase Inhibitor
In additionto the focusonpostsynaptic GABAnreceptors, there
has been considerable interest and, indeed, success in the develop-mentofnew antiepileptic drugs thatmodify GABA disposition in the
brain. Vigabatrin (y-vinyl-GABA),perhaps themostnotableachieve-
ment in this respect, is an enzyme-activated rreversible inhibitor ofGABA transaminase, the main degradative e n m e or GABA. The
drug elevatesbrain GABA levels, and exhibitsanticonvulsantactiv-
ity in a variety of animal seizure models. Moreover, there is nowsubstantial clinical data supporting its efficacy in the treatment of
human eizure disorders (Reynolds, 1992).Although the precisewayin which vigabatrinprevents seizures remainsunclear (Bernasconiet
al., 19881, GABA transaminase inhibition may increase neuronalGABA in a releasable pool, so that larger amounts of GABA aredischarged with stimulation (Gale, 1992).Thus, increased amounts
o f GABA are released in a use-dependem fashion,as needed, during
seizures, It had been believed that tolerance develops only to thesedative side effects ofvigabatrin,but not to its anticonvulsantactiv-
ity (Remy and Beaumont, 1989). Now, however, there is emergingevidence that tolerancemay alsodevelopto the therapeutic effects of
the drug (Martin and Millac, 1993).
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Epilepsy 207
2.3. GABA Uptake BlockersAn alternative approach to increasing synaptic GABA levels is
inhibition of GABA reuptake. A variety of cyclic amino acids,
includingnipecoticacidand guavacine, inhibitglialorneusonal GABAuptake carriers. In general, however, thcse compounds have only
modest potency in vitro and do not enter into the CNS afterparentedadministration. In recent years, n variety of lipophilic analogs ofnipecotic acid and guavacine have been described (Braestrup et al.,
1990;Suzdak, 1993;Andersenet al., 1993).These com po zan d~ wh ichinclude tiagabine, CI-966,NNC-7 11, and SKF lQ0330A---are highly
potent and specific inhibitors of GABA uptake into glia and neurons,but have essentially no activity on other uptake transporters. Unlikenipecotic acidwith its moderate selectivityfo r neuronalGABAuptake,lipophilic GABA uptake inhibitors such as tiagabine show a modestlygreater affinity for glial uptake, but they do inhibit uptake in both celltypes. These compounds are not transported via th e GABA uptake
carrier nor do they stimulate GABA release. Recently, it has been
demonstrated that tiagabine, CI-966, and related lipophilic GABAuptake inhibitors are highEy selective for the GAT-1 cIoned GABA
transporter, the predominant form in rat brain (Burden et al,, 1994).Using in vivo microdialysis in rodents and primates, the systemicadministrationofCI-966 (Tayloretal.,1990)or tiagabine(Fink-Jensenet al., 1992;Sybirska et al., 19933was shown to increase extracellular
GABA overflow. Similar results were obtained in awake human sub-jects with hippocampal microdialysis probes foIlowing acute oral
administrationof tiagabine (During eta]., 1992).Experiments inbrainslicepreparations have demonstrated that Iipephilic GABA reuptake
blockers can prolong the actionofappliedGABAand aEso increase the
amplitude and duration of inhib itoy GABA-mediatedsynaptic poten-
tials (Reckling et aI., 1990;Thompson and Gahwiler, 1992). In addi-
tion, these compounds inhibit epileptiform activity in the slice.Lipsphilic GABA uptake inhibitors have a spectrum s f anti-
convulsant activity in animal seizuremodels that is similar to otherdrugs which act on brain GABA systems, such as the benzodiaz-epines. These compounds are highly effective in protecting against
pentylenetetrazol seizures and may also have activity against sei-
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zures inducedbyotherchemoconvulsants that interfere with GABA-
ergicneurotransrnission, such as the benzodiazepine receptorinverseagonist DMCM (methyl 6,7-dimethoxy-4-ethyl-barboline-3-car-
boxylate). They are far less potent (tiagabine: Nielsen etal., 199 1 ) or
inactive (SW 89976A and SKF 100330-A: Swinyard et al., 1991) in
the maximal electroshocktest. In addition, lipophilic GABA uptakeinhibitors have shown activity in various reflex seizure models(including the photosensitive baboon Papio papio), and in theamygdala and corneal kindIing models (Suzdak, 1993; Swinyardet al., 1991; Smith et al., 1995).At doses higher than those required
to protect against seizures, lipophilic GABA uptake inhibitors pro-duce neurological impairment, as do other drugs that enhance
GABAergic neurotransrnission.However, there is evidence thattol-
erancemay develop to these sideeffects,but not to the anticonvulsantactivity (Suzdak, 1994). LipophiIicGABA uptake inhibitors have a
spectrum of anticonvulsant activity in animal seizure models that isdistinct from the important presently marketed antiepileptic drugs
(Swinyard et aE., 1991 ) . Therefore, it isdifficultto predict fromanimalstudieswhich farms of human epilepsy would be most amenableto therapy with these agents. However, their potency and rela-
tively broad spectrum of activity suggest that they are interestingcandidates for further development.
In human clinical trials, tiagabine has shown activity against
complex partial seizures,with an overall incidence of side effects no
different fiom placebo at therapeutic doses (Mengel, 1994). v o w -ever, adverse side effect such as headache, tiredness, and dizzinesswere obsmedwith increased doses.) Importantly, there was no evi-
denceof
tolerance to the drug's anticonwlsant activity with chronicdosing for up to 12mo. n contrast, in an nitial trial in healthy voIun-teers,CL-966nduced a varietyof severe neurologicaland psychiatricsymptoms (Sedman et al., 1990). There are differences between thepharmacologicalproperties oftiagabineand CI-966 that could accountfor the striking differences in the clinical responses to the two drugs
(see Suzdak, 1993). AItematively, it may simply be that the initial
doses chosen for CI-966 were excessive. It is uncertain whether the
favorable safety record of tiagabine will be maintained in larger tri-
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Epilepsy 209
als. The available in fom ation suggests that cautious optimism about
the potential of lipophilic GABA uptake inhibitors is warranted.
2.4. Potenfintion,of GABA Release
Although drugs that elevate synaptic GABA levels by interfer-
ing with GABA removal mechanisms have anticonvulsant activity,
the continuously elevated GABA levels may have untoward effects.
A theoretically more attractive approach would be to increase the
amount of GABA released with each synaptic stimulus. At present,no selective GABA releasing agents have been described. However,there is some preliminary evidencc that the clinically effective anti-epileptic drug gabapentin could act by such a mechanism.
Although gabapentin was originally synthesized as a GABAanalog, it does not interact with GABAa or GABAR eceptors, isnot
metabolicalIy converted to GABA or a GABA receptor agonist, anddoes not inhibit GABA uptake or degradation (Taylor, 1994).Haw-ever, gabapentin does increase GABA turnover in some brain regions
(Loscher et al., 199 1a) and may increase the release of GABA frombrain slicesin vitro (Gdtz et al., 1993).Recently, it has been observed
that gabapentin can potentiate electrophysiological responses to
released GABA in rat neonatal optic nerve, presumably by increas-ing release from gIia (Kocsis and H o m o u , 1994).A similar effecthas been reported in the hippocampus (Honmou et aI., 1994).
Although these studies with gabapentin and GABA release areintriguing, they are as yet inconclusive. Nevertheless, they serve to
focus attention on the possibility that drugs that enhance GABArelease could have potential as antiepileptic agents.
2.5. Potentiation of GABA and Glycine:Propofol and Chlomethiazole
The anestheticpropofol(2,6-diisopropylphenol) s a structurally
novel barbiturate-like modulator of GABAn receptors (Peduto et aI.,1991). However, in contrast to barbiturates such aspentobarbital, sev-eral recent reportshave suggested that subanesthetic dosesofpropofol:can protectagainstseizures n animal rnodeIs,with minimal behavioralsideeffects (Hasanetal., 1992;al-Haderetal., 1992;Hasan andWolley,
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210 Rogawski
1994).In humans,propofol may be effective in the treatmentof statusepilepticus (Wood et al., 1988), although the drug has also beenreported to cause seizures under certain circumstances (Makela et a].,
1993). Propof01 produces an enhancement of GABA-activated C1-
current and, at high doses, can directly activate GABAAreceptors
(Hales and Lambed, 1991) . In additionto thesebarbiturate-like prop-erties, propofol is also able to potentiate glycinc-evoked currents
(Hales and Larnbert, 1991 ; ut see,Dolin et al., 1992), an actionnotshared by barbiturates, neuroactive steroids, or benzodiazqines.
Another combined GABAA/glycinemodulator forwhich thereis even more clinical information is chlormethiazole, a thiamine
derivative with sedative, hypnotic, anxiolytic, and anticonvulsantproperties (~gren , 986).
ChlormethiazoIeis particularly effective
in the matment of statusepilepticus (even in cases failing torespondto benzodiazepines and barbiturates).Chlomethiazole is a1so used
inpreeclampsia(toxemiaofpregnancy), eclampsia (toxemiaofpreg-nancy with seizures), and the alcohol withdrawal syndrome. En both
animalsand humans, chlormethinzoIehas anticonvulsant activity at
doses that do not produce sedation. Like propofol, chlormethiazole
potentiates responses to bothGABA andglycine,and can also directly
activate GABAAreceptors (Wales and Larnbert, 1992).Propofol andchlonnethiazole uniquely potentiate GABA and glycine, and bothappeartobe effective anticonvuIsantswith low behavioral toxicity at
anticonwlsant doses. The favorable toxicity could be explained ifthe potentiationofGABA and glycine were additive (oreven syner-gistic) for seizure protection, but were not additive for sedative sideeffects. Indeed, it is not apparent that a glycine potentiating drugwould exhibit sedative-hypnotic activity.
3. Interactionswith ExcitatoryAminoAcid Receptor Systems
Acomplementaryapproachto facilitation of synaptic inhibition
is blockade of synaptic excitation. The bulk of fast synaptic excita-tion in the CNS ismediated by the excitatory amino acid glutamate,
acting on AMPA (a-amino-3-hydroxy-5=methyl-4-i~0~au,lepropi0ni~
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acid) and NMDA (N-methyl-D-aspartic acid) receptors. In recent
years, there has been intense interest in the medicinal chemistry of
excitatory am ino acid antagonists because sf their potential in the
treatment of neurological disorders, including epilepsy. The con-viction that excitatory amino acid antagonists have a roIe in epilepsy
therapy is based on extensive in vitro and in vivo evidence that
NMDA and AMPA receptors participate in the expression ofmany
types of epileptic seizures (Rogawski, 1995).Recently, it has been
elegantly shown using microdialysis that glutamate levels areeIevated prior to the onset and during the expression of complexpartial seizures in human subjects (During and Spencer, 1993).Thereis thus strong heoretical support for the potential utility of excitatoryamino acid antagonists in the treatmentof human seizure disorders.However, as yet, this has not been verified in clinical trials.
3.1. NMDA Receptor Antagonists
NMDA receptor antagonists have a broad spectrum of activity
in animal seizuremodels. NMDA antagonistsareparticularlypotent
in the maximal electroshock test in rodents and against reflex sei-zures in rodentsand primates (Chapman and M eldrum, 1993).They
are also protective against pentylenetetrazol and otherchemoconvul-snnts. Thus, the resuIts from animal testing suggest that NMDAantagonists may have utility in the treatment of generalized tonic-
clonic (convulsive) and partial seizures. NMDA antagonists havelower potency against spontan eous absence-like seizures in rodents,so that they are less likely to be of utility in human absence seizures.A particularly interesting feature of NMDA antagonists is their pow-
erful ability to protect against the induction of kindled seizures in
vivo and against kindling-like phenomena in the in vitro hippocam-
pal ~IicepreparationseeRogawski, 1995). This suggests that NMDA
antagonists may prevent the development or progression of some
types of seizures. This property could be of value in certain cIinicaIsituations, such as during the critical period after brain injury or inprogressive childhood epilepsies. The status of efforts to develop asafe and effective NMDA antagonist for use in epilepsy therapy hasbeen recentIy reviewed (Rogawski, 1992).
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3.1.1.CompetitiveNMDA Recognition Site AntagonistsIn 1982, Croucher et al. reported that phosphonic acid competi-
tive NMDA recognition site antagonists were protective against
sound-inducedand minimalpentylenetetrazol eizures inmice. This
important observationstimulated anintensiveresearch effort into the
medicinal chemistry of NMDA receptor antagonists (Rowley and
Leeson, 1992). Numerous structural classes ofNMDA antagonists
havebeen investigated.Perhaps the most mature lineof investigation
is that evolving from the straight chain o-phosphono-a-amino cid
compounds that were the basis of the study by Crouchex et al. (see
Watkins, 1991). The original compounds are very polar and as a
consequence have poor brain penetration.However, cyclic analogswith the amino nitrogen ina six-member ring, as in CGS 19755 (cis-
4-phosphonomethyl-2-piperidine carboxylate; Hutchison et al.,
1989; Lehrnann etal., 1988),or in a piperazine ring,as in CPP (3-[2-
caxboxypiperazin-4-yllpropyl- phosphonate; Davies et al., 1986;Lehmann et al., 1987), had improved systemic activity, and were
even effective orally (Pate1 et al., 1990). It was subsequently foundthat uunsaturation sf the chain, as in CGP 37849 ([El-2-amino-4-methyl-5-phosphono-3-pentanoicacid;Fagg et al., 1990;Schmutzet
al., 1990;De Sarro and De S a m , 1992), or additionof a ketone as inMDL 100453 ~[R]-4-oxo-5-phosphonowaline;hitten et aE., 1990)also resulted in compounds with p o w e f i l systemic anticsnvulsant
activity. Moreover, the carboxyethylester of CGP 37849 (CGP3955 1) showed particularly prolonged oral anticonvulsant activity(De Sarro and De Sarro, 1992). (The reduced analog MDL 10453also is a potent NMDA antagonist;Bigge et al., 1992.) Unsaturation
of the side chain of CPP to form CPPene (Aebischer et al., 1989)
similarly producedan anticonvulsant compound with a long durationof action, The D(-)-enantiorner is the active species of CPPene andhas been used in several studies. D(-)-CPPene has protective activity
in a variety of reflex epilepsy models (Patel et al., 1990; Smith and
Chapman, 1993; Smith et al., 1993; De Sarm and De Sarro, 1993)
and, as is the case forother NMDA antagonists,protects against the
development of kindled seizures (Durmurnuller et al., 1994). Most
competitive NMDA recognition site antagonists have a phosphonic
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Ep i l e p sy 223
acid group as in the original structuresproduced by Watkins (1 991).However, this is not essential to activity as demonstrated byLY233053 and LY275059, n which she phosphonic acid group is
replaced by the bioisosteric tetrazol functionality. LY233053offersgood protection against NMDA and maximal electroshock seizures,
but its duration of action is short (Schoepp et al., 1990a,b;Ornsteinet al,, 1992). The structurally novel bicyclic phosphonic acidLY2746 14has long lasting oral anticonvulsantactivity (Schoepp
e t al., 19913,whereas the corresponding tetmzol LY233536 (Leanderand Ornstein, 1990;Omstein et al., 19901, like LY233053, has amore sapid time course.
CompetitiveNMDA recognition site antagonistsexhibita broadspectrum of activity in animal seizure models. Not unexpectedly,these compounds are highly effective in protecting against seizures
and lethality induced by systemic or intracerebroventricularNMDA.
They are also protective in the maxima1 electroshock test with corn-
parabIe or slightly lower potency (Ferkany et nl . , 1989). Protectionis also conferred against pentylenetemzol-induced clonic seizures,
but typically at somewhat higher doses. However, a structurally
unique cyclic phosphonic acid NPC 12626(2-amino-4,5-[1,2-cyclo-hexyll-7-phosphonoheptanoiG cid) has been describedwhich isless
potent in themaximal electroshocktest than againstNMDA or penty-lenetetrasol seizures (Ferkany et al., 1989). Recently, the highest
potency isomer of NPC 12626 has been identified as the ZR,4R,5Sform (Hamilton et al., 1993). It too shows a reverse ordering ofpotencies in animal seizure models (Ferkany et al., E993).Whetherthis unique profile is related to an unusual selectivity fo r NMDA
receptor subtypes or some other property remains tobe determined.Although diverse NMDA recognitionsiteantagonistswith good
bioavailability and favorable pharmacokinetic properties are now athand, the problemofside effectshas not been so readily solved.Since
NMDA receptors are critical to numerous brain functions, NMDAantagonists can produce a variety of behavioral and neurologicaltoxicities. There are, however, certain encouraging features of thepreclinical profile of competitive NMDA recognition site antag-onists. AnticonvuIsant effects typically occur at doses below those
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that produce motor impairment (De Sarro and De Sarro, 1993;Ferkany et al., 1993). However, the separation between anti-conwlsant activity and motor toxicity is typically smaller than for
otheranticotkvulsantdrugs.Drug discriminationstudies indicate that
the subjective effects ofcompetitive NM DA recognition site antago-
nists in rodents and primates are distinct from those ofdissociativeanesthetic-like NMDA antagonists(Gold and Balster, 1993;Bobelis
and Ralster, 1993). While competitive antagonists do not seem to
have the same propensity for producing certain behavioral sideeffects such as stereotypiesand disturbancesof locomotor behavior
common with dissociative anesthetic-like NMDA antagonists (see
Section 3.1.2.), these stiIl occur.The side effectsmay be especiallyprominent in kindled animals (Loscher and H ~ n a c k , 991a,b).
Tol-erance does not seem to develop to either the therapeutic activity orthe side effects (Smith and Chapman, 1993)-
Despite the various favorable properties ofNMDA recognitionsite antagonists,reports of clinical trials have been disappointing. In
an open-Iabel study of D-CPPene in eight patients with intractablecomplexpartial seizures, a 1patientswithdrew prematurely becauseof side effects. The side effects included poor concentration, seda-
tion, ataxia, depression, dysarthrta (impairment of speech due tomotor impairment), and amnesia (Sveinbjornsdottir et al., 1993).None of the patients experienced a reduction in seizure frequency.
Interestingly, healthy volunteers tolerated much higher doses than
the patients. Thus, as in kindled animals, patients with epilepsy mayhave greater sensitivity to the side effects ofNMDA antagonists.Afinal problem is that competitive antagonists (like the dissociative
anesthetic-like compounds discussed in Section 3.1.2.) can produceneuronal vacuolization and morphological damage in certain brainregions (Olney et al., 1991).
Until recently, it was not appreciated that competitive NM 9Arecognition site antagonists exhibit differing activities at NMDA
receptors composed of different subunit combinations.The informa-
tion now available indicates that this is the case. Thus, CPP appearsto have modestly higher affinity for NMDA receptors composed of
W D A R l - lb subunits that contain a 2 1 -amino acid insert generated
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by alternative splicing of exon 5 (seeMcBain and Mayer, 1994). In
addition to sensitivity to competitive antagonists, this N-terminalvariation determines a variety of functional properties of the NMBA
receptor, including potentiation by ZnZ+nd polyamines and inhibi-tion by protons (HolImann et al., 1993). In the future, it may bepossible to more selectively target specific NMDA receptor subunit
combinations, thus potentially providing for the developmentof less
toxic anticonvulsants.
3.1.2. Channel-BlockingNMDA Receptor Antagonists
The NMDA receptor channel blockers are often referred to as
'kncompetitive" antagonists, because their binding and blockingaction requires the receptor-channel to be gated in the open state.
Occupancy of a binding site within the ionophore of the NMDAreceptor prevents cation flux through the channel, thus producing a
functional block of NMDA receptor responses (MacDonald et al.,
199 1 ). Unlike competitive NMDA recognition site antagonists,uncompetitive antagonistsshare with other noncompetitive antago-
nists of the NMDA receptorthe theoreticaI advantage that their block-ing actionwouldnotbe overcome by high synaptic levelsofgIutamateasmayoccur during seizures. In addition,uncompetitiveantagonistshave the additional theoretical advantage of use-dependence, imply-ing that their inhibitory action may specificallybe potentiatedatsites
of excessive receptor activation. The current status and potentialclinical utiIityofchannel-blocking NM DAreceptor antagonistshaverecently been reviewed (Rogawski, 1992, 1993).
Channel-blocking NMDA receptor antagonists fa11 into two
broad categories:dissociativeanesthetic-like agents and Iow affinityantagonists. Shortly after the discovery of selective competitive
NMDA recognition site antagonists in the early 1980s, the dissocia-tive anestheticsphencyclidine andketamineweredemonstrated to beeffective NMDA receptor antagonists (Anis et al., 1983). The struc-turally dissimilardissociativeanesthetic-likeagentdizocilpine (MK-
801) is also an extremely potent NMDA receptor antagonist. Thesecompounds exert their block in a use-dependentand voltage-depen-dent fashion, indicating that they act by an open-channel mechanism
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216 Rogawski
(Huettner and Bean, f 9881, Like competitive NMDA recognitionsite antagonists, dissociative anestheticsare potent broad spectrumanticonvulsants in a wide variety of animal seizure models (see
Rogawski, 1992).However, at anticonvulsant doses, they producesevere neurobehavioral side effect-including cognitive, sensory,
and various schizophrenia-likedeficits (Krystal et al., 1994)-thatlimit their potential clinical utility. In addition, dissociative anes-
thetics have been reported to cause reversible vacuolization in rat
cortical neurons at low doses (Olney et al., 1989, 19911, and franknecrosis at higher doses (Fix et al.,1993). The propensity of dissocia-tive anesthetics to cause neuronal injury is shared by many NMDA
antagonists, raising doubts as to overall safety of such compounds.
However, caution must be exercised in extrapolating the histo-pathdogical findings obtained in rats to other species. Indeed,NMDA antagonist-induced pathomorphological changes have notbeen documented in primates. Moreover, it is now apparent thatsomeNMDA antagonists may produce only transitory vacuoIization
with no necrosis, or no changes at all.The anticonvuIsant activityof dissociative anesthetics is shared
by a variety ofchannel-blocking NMDA antagonists, someofwhich
are analogs of the dissociative anesthetics and others that are struc-turally distinct. Certain of these compounds have substantiallyreduced behavioral toxicity in animals. For several, there is humanclinical experience documenting an acceptable level of safety. Thesereduced-toxicity channel-blocking NMDA antagonists have beenreferred to as "low affinity" uncompetitive antagonists. However,low affinityper-semay not be the only factor that accounts for their
more favorab le toxicity characteristics(see below).
The existenceof low-toxicity, channel-blocking NMDA antag-onistswas first recognized with the discovery that certain l-phenyl-
cycloalkylamines uch as 1-phenylcyclahexylamine the analog ofphencyclidine substituting a primary amine for the piperidine ring)
and 1-phenylcyclopentylaminewere effectiveanticonvulsants, but
had a reduced propensity to produce motor impairment at anticon-vulsant doses (Rogawski et nl., 1988, 1989; Thurkauf et al., 1990;
Blake et nl . , 1992).Later, an analog of dizocilpine ADCI (5-amino-
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Epilepsy 217
carbonyl-l0,11-dihydro-5H-dibenzo[a,~cyclohepten-5,IO-imine)
was observed to have similarproperties, and also to retard the devel-opment of kindled seizures (Rogawski et al., 1991).These com-
pounds displace binding of dissociative anesthetic receptor Iigands(pH]-[l-(2-thienyl)cyclohexyl]piperidine and [3H]dizocilpine) to
brain membranesandblock NMDA receptor currents in a use-depen-dent and voltage-dependentmanner, ndicating that they are chan-
nel-blocking NMDA antagonists (Rogawski et aI., 1992; Jones
and Rogawski, 1992). However, the binding affinities of thesereduced-toxicity uncompetitiveNMDA receptor antagonists are lower
than thatofphencyclidine and dizocilpine. At equieffective concen-trations, these lower affinity ligands would exhibit faster apparent
rates of block and unblock, and this may, t least in part, account for
the lower toxicity (see Rogawski, 1993). However, reduced bindingaffinity alone cannot completely explain the lower toxicity since
there is an imperfect correlation between binding affinity and thera-
peutic index (Rogawski et al., 1989). Moreover, ketamine, a drug
with strong dissociative anesthetic properties, has a binding affinity
comparable to many of the less toxic channel-blocking agents. In
fact, there isnow evidence that lower toxicity Iigandsmay bind selec-
tivelytoadifferentpopulationofNMDAreceptors thando dissociative
anesthetics (Porter and Greenmyre, 1995).
Recent work with cloned NMDA receptor subunits suggests
that there may be differences among subunit combinations withrespect to their sensitivity to channel-blocking agents (McBain and
Mayex, 19943.For example,assembly of the NMDAR1 subunit withNR2C generates receptors with lower affinity for some channel
blockers than is the case with NR2A orNR2B. In addition,the pres-ence of exon 5 in NMDAR1 (the NMDARl- 1b splice variant; see
Section3.1.1.) confers higher sensitivity to block by dizocilpine andketarnine (Hollmann et al., 1993;Rodriguez-Pazet al., 1995).Moresubtle variations in the structure of NMDA receptors could also
modify the actionsof channel bIockers. A particularlycritical site ofthe NMDARl subunit is the neutral asparagine at position 598. Thiscorrespondstothe editedarginineJgIutamine(QIR) ite in membrane
segment 2 (M2) of AMPA receptors, where a positively charged
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arginine residue in GluR2confers low Ca2+pemeabilityseeSection3.2.2.). Similarly,mutations in NMDAR1 that switch the asparagine
to a positively charged arginine generate receptors resistantto blockby dissociative anesthetics (Kawajiri and Dingledine, 1993;Mori
et al., 1992; Sakurda et a]., 1993). Although there is currently no
evidence forRNA editing ofNMDA receptors at this site (as occursfor AMPA receptor subunits), variations in channel structure inthis or a nearby region of the receptor could have important conse-
quences for the sensitivityto channel blockers.Of course, it remainsto be determined which, if any, structural variation in the NMDAreceptor accounts for the selective binding of low-affinity channel-blocking NMDA antagonists, and, moreover, whether this contrib-
utes to their more favorable toxicity characteristics. Factors otherthan binding affinity and subunit selectivity might also contribute tothe more favorable side-effect profilesofcertain low-affinity NMDA
antagonists (Rogawski, 1993). In particular, synergism betweeneffectson NM DA receptorsandotheranticonvulsant argets couldbe
a factor in some circumstances. For example, ADCI has Na* channelblocking activity similarla carbamazepine (see Section4.1,although
the extent to which this occurs at concentrations relevant to the
anticonvulsant activity is not clear (White, 1994).In recent years, several anticonvulsants of potential clinical
importance have been recognized as low-affinity NMDA receptor
channel-blockers. These include dextrornethorphan and its metabo-
lite dextrorphan;ARL 12495 (formerlyFPL 12495; ,2-diphenyl-2-
propylamine), Ithe metaboliteof the anticonvulsant remacemide; and
the adamantane analog memantine. In contrast to dissociative anes-
thetics, low-affinity channel-blockingNMDA antagonists substitutepoorly, or not at all, for dizocilpine in drug discrimination testing.This indicates that they may not producedissociativeanesthetic-likesubjective effects (Grant, Colombo, Grant, and Rogawski, unpwb-
lished).Moreover, fordextrornethorphan, dextrorphan,remacemide,and memantine, substantial clinical experience indicates that the
compounds can be well tolerated in humans. However, adverseexperiences with all of these compounds have been reported (see
Rogawski, 1993). Controlled therapeutic trials will be necessary to
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Epilepsy 219
verify the efficacy and safety of these low-affinity, uncompetitive
NMDA antagonists in the treatment of seizure disorders. Neverthe-less, there is cause for optimism with this classof compounds.
In addition to their potential in chronic epilepsy therapy,NMDA antagonists may have utility in the treatment of seizures that
occur during ethanol withdrawal (Grant et a!., 1990;Liljequist, 199 I ;
Morrisettetal., 1990).Thismay be in part because of a compensatory
upregulation in the expression of NMDA receptors after chronic
ethanol exposure (Sanna et al., 1993).ADCI isparticularly effectivein this regard (Grant et al., 1992).
3.1.3. GIycine Site Antagonists
It is now well recognized that glycine is a required co-agonistfor activation of the NMDA receptor (Johnson and Ascher, 1987;
KlecknerandDingledine, 1988).Consequently,agents thatcompeti-
tively antagonize the action of glycine would produce a functional
block ofthereceptor and could,therefore,have anticonvulsantactiv-
ity. Several classes of antagonists arenow known which more or lesssefectively block the glycine site (Huettner, 199 I ;Carter, 1992).With intracerebroventricular administration, several of these com-
pounds protect against various types of seizure activity (Singh et al.,
1991; Baron et al., 1990;Koek and Colpaert, 1990;Palfreyman andBaron, 199 1; Bisaga et al., 19933. Recently, Rundfeld et al. ( 1 994)
observed that intraventricular injection of glycine site antagonistsand partial agonistsincreases seizure threshold in arnygdala-kindIed
rats, an effect not observed with other types of NMDA antagonists.A similar positive effect of a glycine site partial agonist (D-cyclos-
erine) was observed against kainate-induced seizures (Baran et al.,1994). These authors suggested that agents active at the glycine siteof the NMDA receptor may be of utiIity in the treatment of seizuretypes that are refractory even to other NMDA antagonists.
A significant impediment to the evaluation of glycine site
antagonists in conventional seizure models has been their lack of
CNS accessibility. This problem now seems to have been largely
overcome, but complete studies of the activity of available com-
pounds in animal seizure models have not yet been reported. Initial
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220 Rogawski
clues to the developmentof systemically active glycine site antago-nists came from the recognition that H A - 9 6 6 (3 -amino-I -
hydroxypyrmlidin-2-one)could be resolved into enantiorners with
distinct pharmacological activities. One enantiomer was a partial,
low-affinity antagonist of the glycine site (Singh et al., 1990;Pullan
et nl., 1990).This R(+)-enantiomer has activity in the electroshockseizure test when administered intravenously, but its therapeutic
index is poor (Vartanian and Taylor, 1991).However, several ana-logs have been synthesized with greater potency, selectivity, andmore favorable toxicity properties, such asL-687,414 (3R-amino- 1 -hydraxy-4R-methylpysrolidin-2-one) (Leeson et al., 1990, 1993;Smith and Meldrum, 1992).Nevertheless, despite intense effort, it
was not possible to produce a compound in this series with suffi-ciently favorable properties to warrant clinical development.Another gIycine site partial agonist with anticonwlsant activity
is 1-aminocyclopropanecarboxyliG cid (ACPC), a particularly highaffinity ligand. ACPC is protective in several seizure models
(SkoEnick eta]., 1989; Witkin and TorEeIla, 1991; Smith et al., 1993;Bisaga et al., 19931, but may not be active in the maximal elec-troshock test. Unlike other glycine site partial agonists with
anticonwlsant properties,ACPC has nearIy full efficacy (about 85%;Watson and Lanthorn, 19901,thus perhaps accounting for its unusualspectrum of activity. Indeed, it is surprising that the drug is anti-
convulsant at all.
Recently, certain 5-nitro quinoxaline-2,3-dioneswere demon-
strated to have highly potent (KI, 10 Rn?l) glycine site blocking
activity and good central availability when administered systemi-cally.These compoundsalso block AMPA receptors, but do sowith
several hundred-fold lower potency (Woodward et al., 1993). Twosuch compounds, 5-nitro-6-rnethyl-7-chloro-2,3-quinoxali~eW C Q X ) and 5-nitm-6,7-dimethyl-2,3-quinoxalinedioneMMDX),have been reported to have activity in the maximal electroshock testat reIatively low systemic doses (Tran et al., 1994). However, theextent to which the weak AMPA receptorblocking activity contrib-
utes to the compounds' anticonvulsant effects i sunclear. The related
quinoxalinedione ACEA-1021 (5-nitro-6,7-dichIoro- 1,4-dihydro-
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Epilepsy 221
2,3-quinoxalinedione) has been reported not to substitute forphencyclidine in drug discrimination testing, indicating hat this classof compounds may not produce dissociative anesthetic-like subjec-tive effects (Balster et al., 1993). It is possible that selective actionsof these compounds at different NMDA receptor subtypes could, inpart, account for the favorable behavioral profile. However, to date,glycine site antagonists have not been reported to have substantialsubunit selectivity.
A series ofrelated structures-the 3-nitro-3,4-dihydro-2-quino-lones-have been described with varying degrees of glycine site orAMPA receptor selectivity. These compounds are based on 7-chloro-kynurenicacid, apotent glycine site antagonist in vitro, but eliminatethe carboxylic acid group that seems to prevent blood-brain barrierpenetration. One of these, L-698,544, exhibited good systemic activ-
ity as an anticonvulsant(EDSO,3.2 mg/kg? p) in the DBA/2 mouse(Carling et al., 1993).Although L-698,544 interacts with the NMDA
(Kh, .7 pkf)and AMPA (Kk,,.2 pM)recognition sites, these inter-actions occur with somewhat lower affinity than for the glycine site(ICso,0.4 1w . prodrug ester of the potent glycine site antagonist5,T-dichlorokynurenic acid has also been reported to have systemicnnticonvulsant activity in the DBAI2 mouse (EDSO,2 mglkg, ip;
Moore etal., 1993).Similarly,another quinolinoneglycine siteantag-onist MDL 104,653(3-phenyl4-hydroxy-T-chlor~-quino~in-2[1H]-
one; McQuaid et al., 1992)has been observed to have anticonvulsantactivity, when administered either intraperitoneally or orally, in
DBAJ2 mice (Chapman et al., 1993).Interestingly, high doses of thecompound produced ataxia and sedation, and the therapeutic ratio
was no better than for other NMDA antagonists.Study of a further series of noncarboxylic acid quinoIinones
resulted in the identification ofL-70 1,273 (3-cyclopropyl-ketone-4-
hydroxyquinolin-2[ 1H]-one), with high potency against audiogenicseizures in D B N 2 mice (4.1rngkg, ip; Rowley et al., 1993).This com-pound has moderately high activity at the glycinesite (IC50,0.42m,but also interacts with the NMDA recognition site (Kbr 3.4 pi%!),
although it is inactive at;AMPA receptors. More recently, a seriesof3'-substituted-3-phenyl analogs of the 4-hydroxyquinolinones were
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222 Rogawski
discovered with nanomolar binding affinities for the glycine site
(Kulagowski et al., 1994). As i s the case for the parent 3-ketones,the 3-phenyl substituted analogs showactivity at the NMDA recog-
nition site but do not block AMPA receptors. These compoundsappear to be the most potent systemicallyactive glycine site antago-
nists described to date, with El350 values <1 mg/kg in the D B N 2mouse modelwhenadministeredeither in~aperitoneallyrorally. It
would appear that these compoundshave favorable toxicity charac-teristics,producingmotor impairmentonly at doses that are substan-tially higher than those that protect against seizures, but this wiHrequire further confirmation. Thus, a variety of potent, and more or
less selective, glycine site antagonists are now available, some o f
which have high systemic potency and excellentoral bioavailability.T remains to be determined if these compounds will be superior toother types of M D A antagonists for seizure therapy. Of particular
interest is thepossibility that the additionalAMPA receptor blockingactivity ofsome of the glycine site antagonists may actually provide
enhanced anticonvulsant activity. As discussed in Section 3 . 2 ,
AMPA receptorblockade can confer apowerful anticondsant effect.
3.1 4.Polyamine SiteAntagonistsThe demonstration by Ransom and Stec (1988) that the poly-
amines spermhe and permidine enhanced binding of ~HJdizocilpine
to NMDA receptors in brain homogenatessuggestedthatpolyarnines
could facilitate gatingof the NMDA receptor.Although polyamineshave multiple effects on NMDA receptors (Rock and Macdonald,1992; Benveniste and Mayer, 19931, a major action is to increase
channel opening frequency via an interaction with a distinct recog-nition site en the NMDA receptor complex (Williams et al., 1991).
The polyarnine facilitatory effect appears to be mediated by an
increase in the affinity for glycine and also by a distinct glycine-independentmechanism (Williamset al., 1994; Zhang et al., 1994b3.
Therehas been interest in developingpolyaminesite antagonists,but
success to date has been limited.
Two related compoundsproposed aspolyamine site antagonists
are theneuroprotective agents ifenprodil and eliprodil (SL 2.0715)
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Epilepsy 223
(Scatton et al., 1994). Ifenprodil and eliprodil are now we11 recog-
nized to be potent noncompetitive NMDA antagonistsboth in vitro
and in vlvo. Electrophysiological studies in cultured hippocampal
neurons havedemonstrated that ifenprodil produces a complex effecton gating of the NMDA receptor channel (Legendre and Westbrook,1991). This action occurs in a manner that is distinct from that of
other NMDA antagonists, but is otherwise poorIy characterized.Although there is considerableevidence that ifenprodil and eliprodil
can functionally interact with polyarnine effects on the NMDAreceptor, it is unlikely that this occurs at a common recognition site
(Ogita et al., 1992). It has instead been proposed that the polyamineand ifenprodiEJeliprodi1binding sitesmay shareoverlapping domainsan the NMDA receptor complex or that the apparent antagonism
occurs because of a functional interaction at distinct sites.Recently, it has been observed that the distribution of PWIifen-
prodil binding sites in brain closely matches the expression of
NMDAR-2B subunit mRNA (Dana et al., 1991). Moreover, ifen-
prodil appears to selectively antagonize NMDA receptorscomposedof NRlA and NR2B subunits, although it can also block NRlA/
NR2A receptors at substantially higher concentrations (Williams,1993). Therefore, at ordinary doses, ifenprodil m ay interact with
only a subpopulation of NMDA receptors. Interestingly, it nowappears that polyamine facilitation is variably expressed depending
on the subunit composition of the NMDA receptor. The 2B subunitisa key subunitin conferring the receptor with polyarnine sensitivity
(Zhang et al., 1994b).
Despite their relatively potent NMDA receptor blocking activ-
ity, ifenprodil and eliprodil appear to have more favorable toxicityprofiles than other NMDA antagonists (Scatton et al., 1994).At
neuroprotective doses, they do not produceneurological impairmentand do not substitute for phencyclidine in drug discrimination studies
or induce amnestic effects in passive avoidance testing. Moreover,clinical trials have indicated that the drugs do not produce psycho-stimulant, amnestic, or psychotomimetic effects in humans. n addi-
tion, eliprodil does not appear to produce pathomorphologicalchanges, that, as has been noted in Section 3.1.2.,are characteristic
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of other NMDA antagonists (Duval et al., 1992). Tt has been sug-gested that the unique subunit selectivityof ifenprodil and eliprodil
may account for their favorable toxicity characteristics.
As is the case for other M D A antagonists, ifenprodil and
eliprodil have a broad spectrum of anticonvulsant activity in animal
seizure models (D e Sarro and De Sarro, 1993; Scatton et al., 1994).These effects, however, occur at doses that are higher than theneuroprotective doses and are nearer to the doses that cause toxiceffects. For example, in the case o f ifenprodil, there is little separa-
tion in the doses that protect against seizures (mouse maximal elec-troshock test ED50,29mgkg, p) and induce motor impairment. For
eliprodil the therapeutic index issomewhatbetter (e lec tmshockED~~,
15 mgikg, ip; rotarodED501
59 rng/kg). (Interestingly, however,eliprodil has been shown o potentiate the anticonvulsantactivity ofthe competitive NMDA recognition site antagonist CGP 37849;
Deren-Wesolek and Maj, 1993.) Thus, t may be that the NMDAreceptor subtype selectivity of ifenprodil/eliprodil s not optimally
suited for seizure protection, at least in the animal models used for
screening.Whetherthis is a characteristic of all functionalpolyamine
antagonists,remains to be determined.
A varietyofothercompoundshave been proposed aspolyamineantagonists, including several polyarnines (Williams et al., 1990)andcertain peptide componentsofmarine snail toxins (Skolnick et al.,
1994).Nevertheless, few of these proposed antagonists are suitable
for evaluating the idea that polyamine antagonism is a viable anti-convulsant strategy. Indeed, several putative polymine site antago-nists have complex effects on the NMDA receptor, includingchannel-blockingactivity, which eonfound any interpretationoftheir
specific polynmine site effects (Donevan et al., 1992;Submmaniamet al., 1992).However, one interesting candidate antagonist is N-(3-
aminopropy1)cyclohexylamine (APCHA), a cyclohexyl diamine. It
has been demonstrated to block the facilitation by spermidine ofNMDA-induced seizures in mice (Chu et al., 1994). Unfortunately,
APCHA may not be active with systemic administration and it has
yet to be demonstrated that this compound acts via a specific inter-
action with the polyamine site.
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Epilepsy 225
There is some evidence that brain polyamine concentrations may
increasewith kindling, either produced electrically (Hayashi et al.,1989)or by repeated treatment with pentylenetetrazol (Hayashi et
al., 1993).However,it remainsundeterminedwhether these increasedlevels contribute to the hyperexcitability of the kindled state. Should
this be the case, the argument supporting the potential use ofpolyamine siteantagonists in seizuretherapy would be strengthened.
3.1.5.Anfagovtists
rat Ofer Sites on heNMDAReceptor Complexand the Combined Acf ons ofFelbamate
on NMDA/GABA, Recep fors
In recent years, a classofNMDA antagonisthas been identifiedin which inhibition is exerted at sites that are distinct from those of
known N M D A receptor coagonists or facilitatory modulators.Indeed, ifenprodiI and eIiprodil are probably best considered amongthis class of NMDA antagonist. Other examples include a series
of n-alkyl diamines that inhibit NMDA receptors by acting at a
nonvoltage dependent, hydrophobicbinding site as well as in n chan-nel-blocking fashion (Subramaniam et al., 1994).Similarly, the anti-convulsantrernacemide may also block NMDA receptors in part bysuch an allosteric action (Submm aniamet aI., 1995a). Felbamate too
is an example of an anticonvulsant that may antagonize NMDAreceptors by an allosteric effect on channeI gating, although a fast
channel-blocking action of the drug may be more important.Although glycine and the glycine site agonist d-serine are able to
functionally reverse the anticonwlsant effects of felbamate in vivo(Hamsworth et al., 1993; Coffin et al., E 994), there is strong evi-
dence that felbamatedoesnot act directly at the glycine site (Rho et aI.,
1994d;Subramaniam et al., 1995b).
As discussed in Section 2. I .2.,felbamate also produces a mod-est potentiation of GABAAreceptor responses within the same range
of concentrations hat it blocks NMDA responses (Rho et al., 1994b3.Both of these effectsoccur at concentrationsof felbamatelikely tobe
present in the brain during antiepileptic therapy. Felbamate exhibitsa broader spectrum of anticonvulsant activity than conventiona1
antiepileptic agents such as phenytoin and carbamazepine. (It con-
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226 Rogawski
fers protection in the maximal electroshock test and also againstseizures induced by pentylenetetrazol; Swinyard et al., 1986.) Clini-cally,the drug has activity in the treatment of partial and secondarilygeneral ized tonic4onic seizures and it is also effective againstrefractory seizures of the Lennox-Gastaut syndrome in children,
which are notoriously difficult to treat. The combination of actionsof felbamateon excitatoryand inhibitory synaptic transmissioncouldaccount for its broad spectrum of activity and favorable side-effectprofile. More specificaIly, it can be postulated that the distinct
actions on NMDA and GABAAreceptors are by themselves belowthe threshold for side effects, but that the actions at the two sitesare
additive or even synergistic against seizures. That a drug such as
felbamate with low neurological toxicity may exert its therapeuticactivity v i a low-affinity interactions with more than one receptorsystem contradicts the conventional view that side-effect reduction
is best achieved by high selectivity and potency. However, foranticonvulsantdrugs that modulate excitability mechanisms criti-
cal to normal brain function, agents with high potency and efficacymay have unacceptable toxicity. (See Section 2.1.1.1. for a moredetailed discussion with reference to partialbenzodiazepine receptor
agonists.) Therefore, the search for drugs that exert low efficacyeffects on more than one receptor seemsto be a worthwhile strategy.
3.2.RMPA Receptor Antagonists
AMPA (non-NMDA) receptors play a key roIe in CNS integra-tion as the prime mediators of fast synaptic excitation. The critical
nature of AMPA receptors is hard to overstate inasmuch as they
participate in virtually every central circuit and,of particular impor-tance here, mediate epileptiform activity in a variety ofmodel sys-
tems (Rogawski, 1994). Consequently, the observation that AMPA
receptor antagonistshave anticonvulsant activity isnot unexpected.
However, at present, it is unclear if AMPA receptor antagonistswill be sufficiently free of toxicity to be clinically useful anti-
convulsants.Nevertheless,thepossibility of selectively targeting thevarious AMPA receptor subtypes provides enormous opportunities
for drug development.
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Epilepsy 227
3.2.1. CornpstifiveAMPA Receptor Anfagonisfs
During the early period of excitatory amino acid receptor
research, AMPA receptor antagonists were unavailable. However, inthe late 1980sthe situation changed: Hanore et al. (1988) deveIapeda series of quinoxaiinediones as selective and relatively potentcompetitive AMPA recognition site antagonists (see Davies and
CoIlingridge, 1990). Although the first quinoxalinediones to be
described were not systemically active, compounds with goodsystemic bioavailabilityarenow available.These include the benzo-
h s e dquinoxnlinedioneNBQX C2,3-dihydroxy-6-nitro-7-sul famoyl-
benzo[F]quinoxaline; Sheardown et al., 1990) and the 6-irnidazol
substituted quinoxaIinedione YM90K (6-[lH-imidazal-1-yll-7-
nitro-2,3-[1H-4~-quinoxalinedione;hmori et al., 1994) that mayhave improved CNS penetration in comparisonwith NBQX. A seriesof isatin oxamines has alsobeen described which are highly selective
AMPA receptor antagonists (Watjen et al., 1993).These compoundshave anticonvulsant activity against AMPA-induced seizuresfollowing intravenousand oral administration. In addition,a substi-
tuted decahydroisoquinoline-3-carboxyliccid has been recently
described with good systemic AMPA receptor blocking activity
(Omstein et al,, 1993). This compound, LY215490 ([3SR,4aRS,
4RS,8aRS]-6-[2-(1H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3-
carboxylic acid), also interacts with the NMDA recognition site, butwith 5- to 10-fold lower potency.
Competitive AMPA recognition site antagonists are protectivein the maximal electroshock test and against seizures induced byvarious chemoconvulsants (Yarnaguchi et al., 1993;Omstein et al.,1993). In addition, these compounds have activity against reflex
seizures in rodents and primates (Chapman et al., 1991;Smith et al.,1991;Meldrum et al,, 1992; Ohmori et al., 1994). In the kindling
model,NBQX has been reported to haveprotectiveactivity, although
it is less potent than in other seizure models (Lbscher et al., 1993).
This is in sharp contrast to NMDA antagonists which are weak or
ineffective against established kindled seizures. Despite its activityagainst kindled seizures,NBQX has no effecton he developmentof
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kindling (DiirmiiIler et aI., 1994). This is another important differ-ence from NMDA antagonists, which, as has already been noted(Section 3.1 .), do protect against kindling devejoprnent.
It has ggnerallybeen found that AMPA receptor antagonists haveneurological, toxicity at anticonvulsant doses, although this varies
depending on the seizuremode1 and test conditions <we Chapmanet al., 199I). Thus, NBQX produced motor impairment at doses that
are similar to those that are protective in the maximal electroshocktest (Yamaguchi et al., 1993).The LY215490 has only a modestlybetter therapeutic ra tio (=2.2) (Omstein et al., 1993).Nevertheless,it would be premature to conclude that AMPA receptor antagonistsare unlikely to have clinical utility in seizure therapy, since block-
ade of AMPA receptorsis
an entirely new therapeutic strategy. Onlythrough clinical trials will it be possible to assess the significanceof the therapeutic ratio values determined from animal testing.
Lascheret al. (1993) observed that low doses of NMDA receptorantagonists synergistically enhance the anticonvulsant ac tivity of
NBQX in the kindlingmodel, withoutproducing anincrease n adverseeffects. Although the basis of thisphenomenon s poorly understood,
it seems reasonable that a combination of NMDA and AMPA receptor
blockade may ultimatelyprove to be the optima1approach forepilepsytherapy. In fact, Iow levels ofNMDA receptor blockade may providean antiepileptogenic effect and may also protect against seizure-induced brain damage, inamanner not obtainedwith AMPA receptorantagonists (Berg et al., 1993).As discussed in Section 3.1.3., many
of the recently described gIycine site antagonists also have various
degrees o f AMPA receptor blocking activity. It will be of interest
to determine if the combined activities provide cEinically superiortherapeutic activity with acceptable side-effect properties.
Another potential approach to obtaining improved anticon-vulsant activity with a reduction in side effects would be to targetAMPA receptor subtypes specifically involved in seizure genera-tion or propagation. Such putative seizure-related AMPA receptor
subunits have yet to be identified. However, there is evidence thatnon-NMDA receptors can be selectively targeted with antagonists.
Thus, he isatin oxime NS- 102 (5-nitro-6,7,8,9-tetmhydrobenzo-
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Epilepsy 229
k]indale-2,3-dione-3-oxime)sa non-NMDA antagonistwith selec-
tivity for the kainate binding subunit GluR6 (Johansen et aI., 1993;
Verdoorn et al., 1994). However, the anticonvulsant profile of this
compound remains to be determined.
3.2.2.NoncornpefitiveAMPA Receptor Antagonists
A novel class of selective AMPA receptor antagonists has
recently been identified that exert their blocking action in a mecha-
nistically distinct fashion from competitive AMPA recognition siteantagonists.These antagonists-typified by the 2,3-benzodiazepine(homophthalazine) G Y M 52466 (1-14-aminophenyll-4-methyl-7,8-
methylenedioxy-5H-2,3-benzsdiazepine)-offer an alternativeapproach for blockade of AMPA receptors with potentially distinc-
tive consequences (Tarnawa et al., 1990; Ouardouz and Durand,
1991;Jones et al., 1992).GYKl52466, unlike the quinoxalinedioneAMPA antagonists, does not interact with the AMPA recognition
site, nor is it a channel blocker. Rather, it appears to block AMPA
receptors in a noncompetitivefashionvia anovel allostericsiteon the
AMPAreceptorcomplex (Doncvanand Rogawski, 1993). The block-ingactionofGYKl52466 is highlyselectiveinvitro, withessentially
no effect on NMDA, metabotropic glutamate, or GABAAreceptorresponses, The lack sf effect on GABAAreceptors is particularlynotable in view of the structural similarity of GYKI 52466 with
conventional 1,4-benzodiazepines see Section 2.1. .).Like competitive AMPA recognition site antagonists, GYKl
52466 has anticonvulsant activity in a broad spectrum of animalseizure models (Chapman et al., 1991; Smith et al., 1991;Yamaguchi
et al., 1993; Steppuhn and Turski, 1993). In some experimentalmodels, GYKI 52466 has improved anticonvulsant activity corn-
pared with NBQX. In others, NBQX appears to have greater
selectivity and potency. One situation where the noncompetitive
antagonists would theoretically be preferable to competitive antago-nists is in protection against seizures associated with high synaptic
glutamate levels (see Rogawski, 1993).Under these conditions, the
synapticallyreleased glutaman would surmount the blocking actionofa competitiveantagonistso that high doses of the antagonistwould
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be required to confer seizure protection. However, these high doseswould be more likely to induce side effects. In contrast, minimaldoses of drugs Iike GYKX 52466 may be effective, since equivalentdegrees of block are achieved whatever the glutamate level.
A series of N-substituted GYKE 52466 analogs has been
described with varying degrees ofAMPA receptor blocking activity(Tarnawa et al., 1993). Two of these analogs with greater in vitroAMPA receptorblocking potencies were found to have correspond-ingly greater invivo anticonvulsantpotencies Donevanetal., 1994).
This supports the view that th e anticonvulsant activity of the 2,3-benzodiazepines is due to AMPA receptor blockade.
Recently, it has been demonstrated that AMPA receptors con-
taining the GluR2 subunit havea linear
or outwardly rectifyingcurrent-voltage relationship and a low permeability for Ca2+.Com-binations lacking GluR2 are inwardlyrectifyingand have a high Ca2+
permeability (Hume et al., 1991; Hollrnann et al., 1991; Verdoornetal., 199I). GYKI 52466 appearstoblock Ca2'-permeable and Ca2+-
impermeable AMPA receptors with equal potency (Donevan andRogawski ,unpublished). This is in contrast to the barbiturate pento-barbital that selectivelyblocks Ca2+-impermeableAMPA receptors
(Taverna et al., 1994)and certain arthropod toxins that are selectivefor Ca2+-permeableAMPA receptors (see Section 3.2.3 .). Interest-ingly,GYKI 52466and itsanalogsappeartohavemuchhigherblock-ing potency for AMPA-sel ective non-NMD A receptor subunits thanforkainatep r e f m g subunits (Patemain et a]., 1995).The mplications
of these various selectivity differences arenot yet well understood.
3.2.3.Channel-BlockingAMPA RecepforAntagonists
At present, no selective channel-blocking AMPA receptorantagonists have been identified. However, certain polyaminearthropod toxins could provide clues to the development of such
compounds.The toxins (such as argiotoxin636,philanthotoxin,and
Joro spider toxin) act as potent noncompetitive antagonistsof verte-
brate AMPA receptors (Brackley et al., 1993;Blaschke et al., 1993).These toxins act in a use- and voltage-dependentmanner suggesting
that they are channel blockers (Herlitze et al., 1993). However, the
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Ep i l e p s y 231
toxins are not selective for AMPA receptors, and indeed their block
ofNMDA receptors is more reliable and oftenmore potent (Priestleyet al., 1989;Ragsdale et al., 1989).A likely reason for the inconsis-
tency ofthe AMPA blocking action is suggestedby the recent discov-ery that th e polyamine toxins selectively block inwardly rectifying
AMPAreceptors(that is,those that lack the G l u m subunit)(Blaschkeet al., 1993; Herlitze et al., 1993).
From the point ofview oftheir use as pharmacological tools, the
fact that the toxins block both NMDA and AMPA receptors is adisadvantage. How ever, this may not be an obstacle to the use of such
compounds as therapeutic agents. As has.been noted previously,
combined NMDAIAMPA receptor blockade may produce a syner-gistic anticonvulsant effect. Moreover, the seIectivity of the toxinsfor inwardly rectifying AMPA receptors may be a distinct advantage.
Sincerectifying AMPA receptors are Ca2+ ermeable, it is not hard to
imagine that they could play a role in seizure generation or in the
neurotoxicity associated with prolonged seizures. In fact,there is sug-
gestive,but by no means conclusive, evidence in support of both pos-sibilities. Thus, ithas recently been reported that amygdaloidkindling
is associated with a 25-30% reduction in G l u m levels in the limbic
forebrain and pirifom coflexlamygdala (but not in the entorhinal cor-
tex or amygdala; Prince et al., 1995).The decrease-which was spe-cific for the GluW subunit-was observed in kindled animals at 24 h
after the last seizure; GluR2 levels had returned tonormal at 1wk and1 mo. imilar changes were not obtained after induction of seizures
with the convulsant pentylenetetrazol. It is conceivable that thedecrease in Glum could be a factor in th e induction, but not themain-
tenance, of kindled seizures. If this is the case, agents such as thepolyarnine toxins which selectively block AM PAreceptors lacking the
G l u m subunit could have interesting antiepileptogenic potential.An additional Iine of experimentation is consistent with the
possibility that GluR2 subunit downreguIation could play a role inseizure-inducedneuropathology.Thus, riedman etal.(19943recentlyreported that persistent seizure activity (status epilepticus) can result
in reduced expression of the GluR2 subunit in hippocampal regionsmost vulnerable to neurodegeneratian. This reduction occurs with a
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time course that parallels theneuronal cell loss,supporting a role for
Ca2+ ermeable AMPA receptors in the seizure-induced pathology.
Polyamine toxin-like agents with specificity for Ca2+-permeable
AMPA receptors might, therefore,be well suitedasneuroprotectants
to ameliorate seizure-induced pathological changes.
Although only limited information isavailable, polyarnine tox-ins and a series of smaI1 mol wt analogs referred to as "araxins" dohave anticonvulsantand neuroprotective activity when administeredintracerebroventricularl or systemically (Seymour andMena, 198 9;
Mueller, personal communication).At therapeutically effectivedoses,the compounds donot appear to produce dissociative anesthetic-likebehavioral or histopathological effects, and do not generalize to
phencyclidine in drug discrimination studies. However,with systemic
administmtion,rhereis poor separationbetween the dosesthatconferseizure protection and induce neurological impairment. In addition,
the toxins may produce significant cardiovascular side effects.
3.3. Metaboiropic G lutam ate Receptors
Metabotropic glutamate receptors are a diverse group o f G-protein-coupled receptors that are structurally and functionally dis-
tinct from other glutamate receptors (Suzdak etal., 1994).In contrastto NMDA and AMPA receptors which are themselves ion channels,rnetabotropicglutamate receptorsact via varioussecondmessengersto indirectly regulate a wide variety of ion channels. The potentia1
roleofmetabotropicglutamatereceptorsas targets foranticonvulsantdrugs is not well defined. Nevertheless, activation of rnetabotropicglutamate receptors with selective agonists can produce, in adult
rodents, limbic-like seizures similar to those observed in kindled
animals (Sacaanand Schoepp, 1992;Tizzano et al., P994). In neona-tal rats, metabotropic agonists can produce frank convulsions(McDonald et al.,1993).Interestingly,however,low doses ofcertainmetabotropic glutamate receptor agonists can have weak anti-convulsant effects (see Thornsen et al., 1994). The anticonvulsanteffectspresumably arise because the rnetabotropic glutamaterecep-tor agonists reduce glutamate release by a presynaptic action on
inhibitory autoreceptors (Glaum and Miller, 1994).
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Recently, a novel seriesof conformationally restricted phenyl-
gIycine analogs have been described which act as competitive antag-onists of at least some metabotropic glutamate receptors(Birse et ai.,
1993; Thornsen and Suzdak, 1993;Ferraguti et al., 1994). One of
these compounds, IS)-4-carboxy-3-hydroxyphenylglycine [SJ-
4C3HPG), has been reported to protect against audiogenic seizuresin DBA/2 mice at doses that do not produce neurological im pa im en t
(Thornsen et al., 1994). This effect occurred with intraventricdar,
but not systemic, administration of the drug. In addition,(S)-4C3HPGdiminished the epileptiform activity observed in rat cortical slicesexposed to Mg2+-free onditions. L-AP3 (L-2-amino-3-phosphono-
propionate), a low potency noncompetitive metabotropic receptorantagonist(Schoepp, 19941,has alsoproduced a weak anticonvulsanteffectfolIowing intraventricular administration (Klitgaard and Jack-
son, 1993). Bath IS)-4C3HPG and L-AP3 can have rnetabotropicglutamate receptor agonist properties under some circumstances(Birse et al., 1993).It is therefore conceivable that the anticonwlsant
activity of these compounds relates, at least in part, to this agonistactivity, possibly by presynaptic effectsan glutamate release. Indeed,
it is not clear at present whether metabotropic receptor agonism,
antagonism, or a combination ofagonist and antagonist effectsat dis-tinct metabotropic receptor types represents the most effectiveanticonvulsant approach. NevertheIess, targeting of the various
metabotropic receptor types with selective agonists and antagonistsprovides interestingopportunitiesfor anticonvulsant drug development.
3.4. GlutanrateRelease Inhibitors
Metabotropic glutamate receptorsaxejust one exampleof a host
of receptors and ion channels of the glutamatergic nerve terminal
that are attractive anticonvulsant targets. It has aiready been notedthat barbiturates might in part exert their anticonvulsant activity viainhibition sf glutamate release (through effects on voltage-depen-
dent Ca2+ hannels). In addition, as discussed in the next section, the
therapeutic effectsof anticonvulsant drugs that interact with voltage-
dependent Na' channels is likely due to some extent to inhibition ofglutamate release. It appears that certain toxins including o-Agn
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IVA and cs-Aga MVIIC, which block Ca2+ hannels in presynapticnerve terminals can have anticonvulsant effectswhen administered
inbacerebroventricularly (Jackson et al., 1994). Moreover, a series
s f novel N,N'-diarylguanidines have been reported to be potent, sys-
temically active glutamate release blockers although their mecha-
nism ofaction s not well understood (Reddy et aI., 1994).Thereare
thus a number of interesting leads to glutamate release antagonists ofpotential clinical utility. The challenge will be to develop agents that
have sufficiently low toxicity to be useful in seizure therapy.
4. Interactions
with Voltage-Dependent NatChannels
A wide variety of anticonvulsant drugs are believed to act, atleast in part, via their effects on voltage-dependent Na* channels.
Phenytoin is perhaps the best studied example. Phenytoin is a reia-
tively weak Na*channel blocker and its ability to inhibit Na+channel
activity is highly dependent on the state of the channel. Therapeuticconcentrationsof the drughave little activity on resting Na'channelsat hyperpolarized membrane potentials. Thus, at a potential of -80
mV, 10 p M henytoin, a concentration at the high end of the range
of free therapeutic plasma levels, would produce no more than 15%block of Na' current (Lang et a!,, 1993). However, there is moresignificant block when Na' channels are repetitively activated or
when the initial membrane potential is a t a more depolarized level.
These properties are believed to reflect the higher affinity ofphenyrain for activated and inactivated channels than for resting
channels (Ragsdale et al., 1991). During high frequency firing, thereis aprogressive accumulationof drug binding as Na*channels cycle
through the activated and inactivated states with each action poten-
tial. In addition, a greater proportion of Na+channels is in the inacti-
vated state at depolarized membrane potentials, thus accountingfor the voltage dependence of block. Thc rate at which phenytoin-
bound Na+ channels recover from inactivation is markedly slowed,
particularly at depolarized potentials (Schwartz and Grigat, 1 989;Kuo and Bean, 1994). This property accounts for the stabilization of
Na+channels in the inactivated state.
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Epi lepsy 235
The precise way in which a modification of Na+channel gatingresults in seizure protection is not we11 understood. However, thefollowing hypothesishas often been proposed. During seizures, neu-
rons fire more rapidIy and are more depolarized than under normalconditions, so that their Na* channels would be more susceptible to
block. This would allow phenytoin to selectively suppress high fre-quency firing. Indeed, at low concentrations, phenytoin is well known
to produce a selective inhibition of repetitive action potential firing,
whereas single action potentials are resistant (McLean andMacdonald, 1983). The effects of phenytoin an Na* channels may
ultimately translate into reduced glutamate-mediated synaptic exci-tation, and this cousd play an important role in its anticonvulsant
activity. In fact, phenytoin inhibits therelease of various neurotrans-mitters, including glutamate from brain slices stimulated by the Wa*
channeI activator veratrine (Leach et al., 1986).
A wide variety of anticonvulsant drugs have a spectrum of
anticon wlsant activity in animal seizure models simiIar to that of
phenytoin (Rogawski and Porter, 1990).Many of these may also act
via an interaction with Na+ channels, and in several cases this has
been confirmed in vitro. For example, lamotrigine, an anticanvuEsanteffective in the treatment of refractory partial seizures (Yuen, 1994),
has a similar profile to phenytoin; it is protective in the maximalelectroshock test but not against pentylenetetrazol-induced clonic
seizures (Miller et al., 1986).At clinically relevant concentrations,lamatrigine has been shown to block repetitive firing of CNS neu-
rons.This effect can be reversed by hyperpolarization of the restingmembrane potential, in a manner similar to that ofphenytoin (Cheunget aI., 1992). In addition, the drug suppresses burst firing m corticalneurons(Leesand Leach, 1993),and inhibits binding o f [3M]batracho-toxinin A 20-a-benzoate, a Iigand for Na*channels, to rat brain synap-
tosomes (Cheung et al,, 1992). In voltage clamp studies, Iamotsigineproduced a use-dependent inhibition of Na+channels and slowed therate of recovery from inactivation, effects similar to those produced
by phenytoin (Lang et al., 1993; Taylor, 1993). Thus, he similaritybetween larnotrigine and phenytoin in animal seizure modeIs is par-alleled by corresponding actions on Na* channels.
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236 Roguwski
Riluzole is another anticonvulsant drugwith a phenytoin-likespectrumofactivity (Mizouleet al., 1985).(Riluzole also hasneuro-protective properties [see,for example, Wahl et al., 19933 as doesphenytoin [Stanton and Moskal, 1991; Hayakawa et al., 19941.)Among tsvariouspharmacological actions, riluzole is a blocker of
voltage-dependent Na+ channels. Interestingly, however, unlikephenytoin, the block produced by riluzole does not occur in a use-dependentfashion, suggesting that it doesnot preferentially bind toactivated Na+ channels. Rather, riluzole has an exceptionally
high (>150-300-foId) selectivity for the inactivated state of theNat channel (Benoit and Escande, 1991). These results withriluzole indica te that stabilization of the inactivatedstateo f he Na+
channel may be a particularly critical factor in the anticonvulsantactivity of phenytoin.Severalother anticonvulsant drugs with a phenytoin-Iike spec-
trum of anticonvulsantactivity interactwith Na+channelsin a fash-ionsimilartophenytoin. These include carbamaqine (Ragsdale etal.,
1991;Lang et al., 1993),ralitoline (Rock t al., 1991; Fischer et al.,1992),and flunarizine (Kfskin et al., 1993). In addition, the antican-
vulsant U 54494A (3,4-dichloro-N-methyl-N-[2-(1yrraIidiny1)-
cyclohexylJbenzarnide)(Zhu and Im,1992), its two major activemetabolites (Zhu et al., 1993);and several other structurally relatedbenzarnides with anticonvulsant properties (Zhu et al., 1992) have
been s h o w to interact with Na' channels in a voltage- and use-
dependentfashion, similarlyto phenytoin. The success in identifyingphenytoin-Iike anticonvulsantsisprobably a result of thewidespread
use of the maximal electroshock test as a screening method (inas-
much as the test is highly sensitive to such agents). Since there arealready a large number of safeand effective anticonvu1santdrugs ofthis type, the development of additional phenytoin-like compounds
may not seem be a high priority.However, it would be reasonable to
search for drugs that produce phenytoin-like effects in combinationwith other pharmacological activities hat result in seizureprotection
(forexample,potentiation of GABA or inhibitionof excitatoryaminoacid transmission). The major acute neurologica1 doxicity of
phenytoin is xeferabIe to cerebellar dysfunction, possibly because
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Epilepsy 239
ATP levels in substantia n i p eurons that would activateGTPchan-
nels and depressGABA release. The overall effectwould be to obvi-ate the critical role played by the substantia nigra in the control of
seizure spread (Gale, 1985, 1992). In hypoglycemia, reduced blood
glucose would also lead to diminished intraceilular ATP levels and
a similar inactivationof the substantia nigm seizure-control mecha-nism, perhaps contributing to hypoglycemic seizures.
In other brain regions such as the hippocampus, Knw channel
activation could serve to inhibit seizureactivity. Thus, cromakalimreduced bursting ofhippocampa1 neurons in the in vitro slice prepa-ration (Alzheirner and ten Bruggencate, 1988) and in cell culture(Simon and Lin, 1993). However, in other situations the drug failedto affect hippocampal epileptiformdischarges,although it was able
to inhibit the response to anoxia (Mattia et al., I 994). There are afew reports that intraventricnEarly administered cromakalim canprotect against seizures in certain in vivo chemoconvulsantmodels
(Gandolfo et al., I989a,b; Del Pozo et al., 1990; Popoli et al., 1991),but these reports require confirmation with more traditional anti-convulsant screening tests. As of yet, no K* channel opener drug hasbeen demonstrated to have CNS ctivity following systemic adrnin-
istration. Recently, however, benzopyrans structuraIly related tocromakalim have been described with oral anticonvulsant activity in
the maximal electroshock test (Evans et al., 1992). Whether this
anticonvulsant activity occurs as a result o f effects on K+ hannelsremains to be determined.
TheKt hannel opener drugs represent an interesting directionfor anticonvulsant drug development. However, there are a number
of impediments that must be overcome before this strategy can beconsidered seriously. As noted, blood-brain barrier permeable ana-
logs are required. Assuming such compounds become available,
nonselective K+ hannel opener drugs could theoretically haveproconvulsant effectsmediated, for example, by the substantia nigra.In addition, there isevidence that some K+channel openerscan block
certain voltage-dependent K+channel types that might predispose to
seizures (Politiet al., 1993).Atpresent, thepotential utility of K+chan-nel opener drugs in epilepsy therapy is uncertain.
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Interestingly, however, there are a few reports in the literature
that suggest that presently availableanticonvulsant drugs may act byenhancing K* channel function. For example, it has been proposedthat the tetronic acid derivative losigamone could protect against
seizures by such a mechanism (Klihr and Heinemann, 1990). In
addition,there is a report indicating thatcarbamazepinemay enhance
a K+ current in neocortical neurons (Zona et al., 1990),However,until further confirmatory data is obtained, these observations must
be considered preliminary.
6.Adenosine Agonists
andRelease-EnhancingAgents
Adenosine is a powerful endogenous inhibitory neuro-modulator that isnormally present in the extracellularenvironment
at a concentration of about 1 ph4 Zetterstrorn etal., 1982; Greeneand Haas, 1991). Adenosine exerts its inhibitory action on CNSexcitability by direct (postsynaptic) hyperpolarization of neuronsand by inhibition of synaptic release,particularly of glutamate, viaadenosine receptors on excitatory nerve terminals (Proctor and
Dunwiddie, 1987). These actions are primarily mediated by aden-osine receptors of the A1 type (McCabe and Scholfield, 1985). Dur-ing seizure activity, adenosine levels increase dramatically, which
has led to the proposal that the adenosine may mediate seizure
arrest and postictal refractoriness (Lewin and Bleck, 1981;Dragunow, 1986; Whitcomb et al., 1990; During and Spencer,
1992). A recent study in the hippocampal dice preparation has
suggested that glutamate acting on NMDA receptors can stimulateadenosine release from interneurons (Manzoni et al., 1994). How-ever, the extent to which this accounts for the adenosine released
during seizures in the hippocampus or elsewhere remains uncer-tain. Evidence that endogenous adenosine release protects againstseizure activity is the well-known proconvuIsant activity o fadenosine A I antagonists (Albertson et al., 1983; Murray et al.,
1985). Conversely, treatments that increase adenosine levels or its
actions on inhibitory mechanisms may be effective in preventing
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Epilepsy
seizures. For example, studies in a hippocampal slice preparationhave demonsbatedthat adenosine can suppress epileptifom activity(Dunwiddie, 1980; Lee et al., 1984; Ault and Wang, 19X6),whereas
blockade of adenosine receptors induces sustained interictal dis-
charge and seizure-like activity (Thompson et al., I 992; Alzheimeret al., 1993). There is evidence that adenosine selectively depresses
excitatory but not inhibitory synaptic transmission (Yoon and
Rothman, 1991; Thompson ct a]., 1992;Katchman and Hershkowitz,
1993). The selectivity for excitatory transmission provides a mecha-nism for adenosine's superior anticonvulsant activity in comparison
with other presynaptic modulators (for example, GABABagonists)that may reduce inhibitory as well as excitatory synaptic events.
Much evidence from in vivo experimental models demonstrates
that adenosine receptor stimulation can modulate seizure activity.
Adenosine itself has weak anticonvulsantpropeaies because it hasan extremeIy short biological half-life (5-6 ) and probably pen-etratesthe blood-brain barrier poorly (Rudolphi et al.. 1992).Never-theless, adenosine can protect against audiogenic seizures in mice(Maitreet al., 1974)and alsoprolongs the latency to pentyleneeetrazol
seizures (Dunwiddie and Worth, 1982). Selective adenosine A 1
receptor agonis t s - such a s L-phenylisopropyladenosine, cyclo-hexyladenosine, and 2-chloroadenosine-have much greater anti-convulsant potency. These compounds have been reported to have
activity in the maximal electroshock test (Wiesner and Zimring,1994). In addition, they protect against seizures induced by pentylene-
telrazol (Dunwiddie and Worth, 1982; Murray et al., 1985); bicu-cullfne (Zhang et al., 1994);penicillin (Niglio eta]., 1988);DMCM,
a benzodiazepine receptor inverse agonist (Petersen, 1991);
hornocysteine,a putative adenosine sequestering agent (hlarangsset aI., 1990); and 4-aminopyridine (Jackson et aI., 1994). In addition,
adenosine agonists prevent the development of kindling induced byelectrical stimulation of the amygdala (Dragunow and Goddard,1984) or by the j3-carboline FG 7142 (Stephens and Weidmann,
1989). In contrast, adenosine agonists have variable activity againstseizures in fully kindled animals (Barraco et al., 1984; Rosen andBerman, 1985). Conventional anticonvulsant drugs generally do not
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interfere with kindling development, although NMDA antagonistshave a p a w e A l antiepileptogeniceffect (seeSection 3.1 .).Thus, theability of adenosine agonists to prevent kindling developmentcouldbe related to their inhibition of excitatory amino acid release and a
consequent reduction in the activation of NMDA receptors.
Despite the effectiveness of adenosine A1 agonists in animalseizure models, it is unlikely that these compounds would be clini-cally useful anticonvulsants. Adenosine A l agonistshave powerfuIcardiovascular effects as a result of their actions on peripheral
adenosinereceptors in the heart and vascufature. Even iftheseperiph-era1side effectscouldbe overcome(for example by coadministratian
of a blood-brain barrier impermeable adenosine antagonist such as
8-p-sulfophenyltheophylline), adenosine agonists at anticonvulsantdoses may produce strong sedative effects that would limit theirclinical utility (Dunwiddie and Worth, 1982).Consequently,alterna-
tive strategies wilt need to be developed. One approach is to utilizeinhibitors of adenosine inactivation. These may specifically targetepileptic brain regions since seizure activity is accompaniedby localrelease of adenosine. Such agents would theoretically potentiate the
protective effects of adenosine where needed, without producing
untoward side effects (since release of adenosine may be less signifi-cant under nonepileptic conditions). There are multiple nucleosidetransport (uptake) systems in brain that inactivate released aden-
osine. Electrophysiological studies in the brain slice preparationshave indicated that adenosineuptakeinhibitors such as dipyridamole,dilazep, nitrobenzylthioguanosine, nitrobenzylthioinosine, hexa-
bendine, and soluflazine can potentiate the inhibitory effects ofexogenous adenosine (Sanderson and Scholfield, 1986;Ashton et at.,1987) and reduce epileptiform activity (Ashton et al., 1988). How-ever, adenosine uptake inhibitors generallyhave little effect on nor-mal synaptic transmission. Moreover, microinjection of severaladenosine uptake inhibitors into the rat prepiriform cortex reduced
bicuculline-induced seizures (Zhang et al., 1993). n u s , adenosine
uptake inhibition is a potentially promising anticonwlsant strategy,
However, the available adenosineuptake inhibitors are generally of
low potency or do not penetrate the blood-brain barrier. Another
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Epilepsy 243
approach to selectively enhance endogenous adenosine levels is to
inhibit adenosine metabolism with, for example, inhibitors of aden-osine kinase (such as 5'-amino-5'-deoxyadenosine) or adenosine
deaminase (such as 2'-deoxycoformycin). Although such enzymeinhibitorshave anticonvulsant activity when njected locally (Zhang
et a!., 19931, there is no evidence that they are effective with systemicadministration. Finally, the purine precursor 5-amino-4-irnidazolecarboxarnide riboside (AICAr) (which increases adenosine levels
during ATP catabolism, as may occur in a seizure focus), has weakanticonvulsant activity that can be enhanced by the adenosine uptake
blocker mioflazine (Marangos et al., 1990).AICAr has low bloo&
brain barrier permeability; it will be necessary to develop analogswith improved bioavailability before evaluating the potential of thisapproach. In sum, denosine release enhancement-whether by
adenosine uptake blockade, inhibition of adenosine metabolism, orpromotion of adenosine release (as may occur with the xanthine
oxidase inhibitor oxyputinal; Rudolphi et al., 1992)-would appear
to be a worthwhile investigational approach for anticonvulsant drugdevelopment.
7.The Special Problem of Absence Epilepsy
Absence epilepsy, commonly referred to aspetit mal, is a child-hood neurologicaI disorder characterized by episodes of sudden loss
of awareness lasting 3-10 (Penry et aI., 1975). A child exhibitingan absence attack becomes immobile, stares, and may display anautomatism such as eyelid fluttering or a slightmovement of the face.
There is no loss of body tone (falling), as in generalized tonic-clonic
seizures. Absence seizures have a characteristic electroencephalo-graphic signature consisting of bilateral, symmetrical, synchronous,3 Hz spike-wavebursts. The disorder israre (constitutingperhaps 8%of patients with childhood epilepsy) and usually self-limiting(absence seizures typically remit by adolescence). Absence seizuresare fundamentally different from other types of human epilepsies in
several respects. For the purposes of this discussion, the most impor-tant difference is the unique pharmacologica1 responsiveness ofabsence seizures. Ethosuxirnide, a drug with little activity in other
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seizure types, is highIy effective in the treatmentofabsence seizures.Conversely, absence seizures are worsened by antiepif eptic drugs,such as phenytoin and carbamazepine, that are effective in general-ized convulsive and partial epilepsies,This pharmacologicalevidence
provides strong support for the concept that the pathophysiological
mechanisms underlying absence seizures are distinct from those ofgeneralized convulsive or partial epilepsies. Indeed, absence sei-zures are beIieved to represent a disorder of corticothalarnicrhyth-
micity, as originalIy proposed in the corticoreticular hypothesis ofGloor (1968). Therefore, the brain systemsmeditating absence sei-
zures may be entirely distinct from those that participate in other
seizure types,
Current understanding of absence seizure mechanisms derivesfrornextensive studiesofGloorand his colleagueswith the penicillinmodel of generalized spike-and-wave in the cat (Gloor, E 984).Thesestudieswere based on the historic work of Penfield and Jasper in the
1940sand 1950s (see Jasper, 1991 ) on centrencephalicseizures(i.e.,
seizures hat arise in both hemispheres simultaneously and are asso-ciated with immediate Ioss ofconsciousness,as in absence seizures).Itwas hypothesized by Penfield and Jasper that centrencephalic sei-
zuresaregenerated by activity in subcortical structures,including thethalamus, with widespreadprojections to the cortex.This hypothesis
was refined by Gloot, who proposed that the cortex and thalamus
acted in concert during generalized seizures. Simultaneous record-
ings in the cortex and thalamus of cats treated with penicillin dem-onstrated a pattern of firing during each burst consistent with the
circulation of impulse flow within a loop between thalamus and
cortex (Avoli et al., 1983; Avoli,1987). Tn agreement with this ideawas the observation that both cortex and thalamus ate required for
spike-and-wave discharges: surgical removal or pharmacologicalinhibition of either eliminates epileptifom activity. The criticalinvolvement of cortex and thalamus has now been confirmed in a
brain slice preparation (Coulter and Lee, 1993) and in the geneticabsence epilepsy rat from Strasbourg (GAERS), a more realistic
model of human absence epilepsy than the penicillin model in the cat
(Marescaux et al., 199213).
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Epilepsy 245
A more detailed understanding of the cellular events in genera-tion of the spike-wave discharges by the thalamocortical circuit hascome from electrophysiological (voltage clamp) studies of thalamic
neurons and, more recently, from modeling of the membrane poten-tial of these cells using parameters derived from voltage clamp
experiments (Wang et al., 1991;Huguenard and McCormick, 1992).Burst firing in thalamic neurons is dependent on a slow potential,referred to as the "low-threshold spike" (LTS), mediated by T-type
voltage-dependent Ca2+ hannels (Jahnsen and LlinBs, 1984a,b;Suzuki and Rogawski, 1989;CouIter et al., 1989a). Strong hyperpo-larization is required to prime (de-inactivate) T-type Ca2+ hannelsthat are normally inactivated at resting potential. Activation of theLTS in thalamocorticalrelay neurons is, in turn, dependent on inhibi-tory drive from thalamic reticular nucleus neurons (Huguenard andPrince, 1992b$,These neuronshave intrinsic pacemaker activity that
generates rhythmic sequences of oscillatory bursts (Bal an dMcComick, 1993). Interestingly, this burst firing is also dependenton aT-typeCa2'current,but with somewhatdifferent properties fromthat present in relay neurons (Huguenard and Prince, 1992b). Tha-lamic reticularnucleus neurons are GABAergic. These neurons formrecurrent inhibitory connections among themselves, and also pro-vide a powerfuI inhibitory input necessary to de-inactivate T-typeCaZ+ hannelsof relay neurons. The prolonged inhibitory postsynap-
tic potential (IPSP) in relay neurons is probably mediated by GABAAand GABAB receptors (Thornson, 1988;Soltesz et al., 1989).Pres-
ently, the role of GABAB eceptors in regulating the norm al firingof relayneurons is poorly defined (McCormick, 1992; von Krosigk
et al., 1993). However, during seizure activity (as can be inducedwith GABAA receptor antagonists in thalamic slices), GABAB
receptors appear to play a critical role in synchronizing the firing(von Krosigk et al., 1993).
7.1. T-Type Vo liage-Dependent Ca2+Channel Antagonists
The fundamental insights from elech-ophysiological tudies ofthe thalamus have led to a mechanistic understanding of the selectiveantiabsence drug ethosuximide and have also suggested strategies
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for the development ofnew medicationsforabsence seizures.Thus,Coulter et a!. (1989b) demonstrated that ethosuximide produces amodest (up to 40%)reduction in amplitudeof the T-type Ca2+ ur-rent in thalamicneurons see alsoKostyuk et al., 1992;Huguenard
and Prince, 1994).The ECso for this effect is 200 pI4and there is
a roughly 2&35% reduction in Ca2+ urrent at ethosuximide con-centrationswithin theclinically relevant concentration range. Corn-puter simulations of individual thalamic neurons have shown that
even smaller reductions in the T-type Ca2+ urrent could result in adiminutionof the LTS Lytton and Sejnowski, 1992).These resultssupport the hypothesis that ethosuximide's effects on the T-type
Ca2+ urrent selectivelyalter the dynamics of slow bursting in tha-
lamic relay neurons that could lead to protection against absence
seizures. Additionally, however, ethosuximide probably also actson the T-type Ca" current in nucleus reticularis neurons to reducetheir burst firing (Huguenard and Prince, 1992a). The effect onreticularis neurons would diminish the hyperpolarizing influence
that these cells generate in relay neurons and that is necessary fortheir burst firing. The dual action of exthosuximide an nucleus
reticularis and relay neurons would act in concert to interrupt
thalamic bursting, and in turn thalarnocortical synchronizationduring absence seizures.
In additionto ethosuximide,dimethadione (the active metab-
olite of the anti-absence drug trirnethadione) and methylphenyl-succinimide (the active metabolite o f another anti-absence drugmethsuxirnide) have been shown to cause a reduction in theT-type Ca2+current in both thalamic relay-neurons and nucleusreticularis neurons (Coulter et al., 1990; Huguenard and Prince,
1992a). In contrast, valproate, an agent that is also highly effec-tive in the treatment of absence seizures, has not been found t o
affect T-type Ca2+currents in thalamic neurons at clinically rel-evant concentrations. Nonetheless, the drug has been reported toaffecta similar current in a peripheral neuron (Kelly et al., 1 990).Whether valproate's activity as an absence agent relates to
effects on Ca2+ hannels or to effects on another molecular target
is unknown.
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7.2. GABA, Receptor Antagonists
The critical role of GABAR receptors in the generation of
absence seizureshas been demonstrated in several animal models bythe use of selective GABAs agonists and antagonists. Thus, the
GABAs agonist baclofen enhanced, and the GABABantagonistCGP35348 inhibited, absence-like seizures in y-hydroxybutyrate-treated
rats (Snead, 1992), he GAERS rat (Liu et al., 1992;Marcscaux et al.,
1992a), and the lethargic mouse (Hosford etal., 1992). nterestingly,
in the lethargic mouse there is evidence for a genetic defect resultingin the overexpression o f GABABreceptors. These animals show a
modest increase in GABAe receptor density as assessed with
radioligand binding and also exhibit evidence of enhanced GABAR
receptor functional activity in brain slice recordings (Hosford et al.,
1992). In the GAERS rat, however, no such alteration in GABAB
receptorswasobserved (Spreaficoet:al., 19933.Thus,while absence-
like seizures can occur in animal models as a result of a variety ofunderlying pathophysiological mechanisms, GABAe receptorantagonists appear to be effective in all instances .
The precise site at which GABAAantagonists exert their anti-
absence activity has not been defined with certainty. However, elec-
trophysiological studies in thalamic slices hav e supported thehypothesis that,during eizure activity, synapticactivationofGABAR
receptors generates the hyperpolarization necessary to de-inactivate
the T-type CaZ+urrent (vonKrosigk et al., 1993).Interruptionofthishyperpolarizing influence by antagonists would prevent the seizureactivity, but would not affect normal ongoing activity, which seems
Iessdependent on GABAB eceptor activation. Although there isnowextensive experimental evidence supporting the potentiaI cIinicaZutility of GABABantagonists as anti-absence agents, this will needto be confirmed in clinical trials, now in progress.
7.3.Potential Anti-A bsence Drugsif UnknownMecha~ i sm
There are a variety of compounds that have an anticonvulsant
profile in animal seizure models simiIar to that ofexthosuximide,butwhose mechanism of action is unknown. One uch compound is the
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imidazopyridine AHR- 12245 (2-[4-chEorophenyl]-3H-imadam[4,5-
blpyidine-3-acetamid) (Johnson et al., 1991). Like ethosuxirnide,
AHR- 12245 isactive orallyagainstpentylenetetmzal seizuresinbothmice and rats, but is ineffective in the maximal electroshock test.However, AHR- E 2245 has a substantially greater therapeutic index
than ethosuxirnideand is thereforean interestingcandidate for evalu-ation in the treatment of generalized absence seizures.Asnotedin Sections2.1.4.and 2.2.6.,GABA-potentiating m u -
roactive steroids and IoreclezaEe have profiles of activity similar tothatofethosuxirnide.Whether these compoundswill prove useful in
the treatment of absence seizures remains unknown.
ReferencesAebischcrB,Frey P, Haerter H-P, Herrling PI, Mueller W, OlvennanHJ,Watkins JC
( 1 989) ynthesis and NMDA antagonistic properties o f the enantiomers of 4-
(3-phosphonopropyl)piperazine-2-catboxylic cid (CPP) and of the unsaturatedanalogue (E)-4-(3-phosphonopmp-2-enyl)piperazine-2-caboxylicacid (CPP-ene).Helv Chim Arra 72:1043-1 05 1.
Aird RB,Gordan GS (195 1 ) Anticonvulsive propefiies of desoxycorticasterone.
JAMA 145:715-719.
al-Hader A, Hasan M, HasanZ 11992)The omparativeeffects ofpropofo1,thiopental,
and diazepam, administered intravenously, on pentylenetetrazol seizure thresholdin the rabbit. Life Sci 513779-786.
Albertson TE, Stark LG, oy RM,Bawycr JF (19X3)Aminophyllinc and kindled
seizures. Exp Neurol 81:703-713.
Alzheimer C, Sutor B, en BmggencateG 1 993) Disinhibitionof hippocampalCA3neurons inducedby suppression of an adenosineA1 receptor-mediatedinhibitory
tonus: pre- and postsynaptic components.Neuroscience57:565-575.Alzheimer C, ten BruggtncateG 1988) Actions of BRL 34915 (Cmrnakalim)upan
convulsive discharges in guinea pig hippocampal slices. Naunyn-Schmiedeberg'sArch Pbamncol 337:429-434.
Amoroso A, Schmid-Antomarchi H, osset M, Lazdunski M (1990) Glucose,sulfonylureas, and neumtransmittcrrelease: rote of ATP-sensitive K+ channels.Science 247 :852454 .
Andersen KE, Braestrup C, Granwald FC, Jrargensen AS, Bielsen EB, Sonnewald U,Sarrenscn PO, uzdak PD, Knutsen LJS (1993) The synthesis of novel GABAuptake inhibitors. 1 . Elucidation of the structure-activity studies leading to the
choice of ( R ) - 1 - [ 4 , 4 - B i s ( 3 - m e t h y 1 - 2 - t h i e n y l ) - 3 - b ~ a r b o x y l i cacid (riagabine) as an anticonvulsantdrug candidate. J Med Chem 36:1716-1 725.
Anis NA, Berry SC,Burton NR, Lodge D 1983) The dissociative anaesthetics,ketaminc and phencyclidine, selectively reduce excitation of central mammalianneuroncs by N-methyl-aspartate. RFJ Pharmacol T9 :565575 .
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 57/81
Epilepsy
Ashcroft S J H , Ashcroft FM (1990) Properties and functions of ATP-sensitive K-
channels. Cejl Signal 2: 197-2 14.Ashford MLJ, Boden PR, Trehernc JM (1990a) Glucose-induced excitation of hypo-
thalamic neurones i s mediated by ATP-sensitive K + channels. PflUgers Arch4 15:479-483.
Ashford MU, oden PR, TreherneJM(1990b) albutamide excites ratglucoreceptiveventromedial hypothalamic neurones by indirect inhibidon of ATP-K+ channcls.Br J Phannacol 101:531-540.
Ashton D, e Prins E,Willems R,Van Belle H, Wauquier A (1988) Anticonvulsantaction of the nucleosidc transpon inhibitor, soluflazine, on synaptic and nen-
synap tic epilcptoganesis in the guinea-pig hippocampus. Epilepsy Res2:65-7
1.Ashtan D, Franscn J , Hecrcs J, Clinckc GH, Janssen PA (1992) I n vivn studies on thcmechanism of action of the broad spectrum anticonvulsant loreclezolc. EpilepsyRes 3 1:27-36.
Ashron D, Willcrns R, De Prins E, VanBelle H,Wauquier A (1987)The nuclcoside-transport inhibitor soluflazine (R 64 719) increases the effects of adenosine in theguinca-pig hippocampal slice and is antagonized by adenosine deaminase. Eur JPharrnacol 142:403408.
Ates N, van Luijtelmr ELJM, Drinkenburg WHIM, Vosscn JMH, Coenen AM L
(1992)Effects of lorectezoleon epileptic activity andon EEG and behaviourin ats
with absence seizures. Epilepsy Res 13:43-48.Ault B, ang CM ( 1 986) Adenosine inhibits epileptiform activity arising m hippoc-
ampal area CA3. Br J Pharmacol8T:h95-703.Avoli M ( 1 987)Mechanisms of generalized epilepsy with spike and wave discharge.
Electroencephalogr Clin Ncurophysiol 39(SuppI): 184-1 90.
Avoli M , Gloor P, ostopoulos G, otrnan J (1983)An analys is ofpenicifIin-inducedgeneralized sp ike and wave discharges using simultaneous recordings of corticaland thalamic single neurones. J Neurophysiol 50:819-837.
Ba1 T. McCormick DA (1993) Mechanisms of oscillatory activity in guinea-pig
nucleus reticularis thalami in vitro: a mammalian pacemaker. J Physiol (Lond)46R:h6949 1.
Balster RL, Grech DM, Mansbach RS, Li H, Weber E 1 993) Behavioral studies onthe novel griycine-site NMDA antagonists ACEA-1011 and ACEA- 1021. SocNeurosci Abstr 19:472.
Baran H, Loescher W, Mevissen M 1 994)The glycine-NMDA receptor partial ago-nist D-cycloswine blocks kainate-induced seizures in rats. Comparison with MK-
801 and diazepam. Brain Res 652: 195-200.Baron BM, Harrison BL. Miller FP, McDonald IA, SalituroFG, SchmidtCJ, orensen
SM,White HS, Palfreyman M G (1990)Activity of 5,7-dichlorokynurenic acid, a
potent antagonist at the N-methyl-D-aspartate receptor-associated glycinebindingsite. Mol Pharmacol 38554-56 .
Barraco RA. Swanson TH, Phillis JW, Beman RF (1984) Anticonvulsant effectsofadenosine analogues on amygdaloid-kindled seizures in rats. Neurosci Lett46:317-322.
Belelli D, Bolger ME, Gee KW (1989) Anticonvulsant profile of the progesteronemetabolite 5 al ha- re nan-3 111 h$-01-20-0ne. Eur J Pharmacol 166:325-329.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 58/81
250 Rogawski
Belelli D, Lan NC, Gee KW (1990) Anticonvulsant steroids and th e GABA l
benzodiazepine receptor-chloride ionophorc complex. Neurosci Biobehav Rev1 4 315-322.
Benavides J, Peny B, Dubois A, Perrault G, Morel E, Zivkovic B, catton B 1988)I n vivo interaction of zolpidem with central benzodiaepine (RZD) binding sites(asLbeled by ['HIRo 15-1788) in the mousebrain, Preferential affinityofzolpidem
for thc w , (BZD,) subtype. J PhamacoI Exp Ther 245: 1033-1041.Benavidcs 5, Pcny B, Ruano D, Vitorica J, Scatton 0 (19933 Comparative autoradio-
graphic distribution of central o benzodiazep ine) modulatory site subtypes withhigh, intermcdiatc and low affinity for nolpidcm and alpidem, Rrnin RCS
604:24&250.
Btnoit E, Escande D (1991) iluzole specifically blocks inactivated Na channels inmyelinated nerve fibre. Pflllgcrs Arch 4 19:603409.
Benveniste M, MayesMI. 1 993)Multiple effects of spermine onN-methyl-D-aspar-tic acid receptor responsesof rat cultured hippocampal neurones. J Physiol (Lond)464: 131-163.
Berg M. BruhnT, ohansenFF.Diemer NH (1993) Kainic acid-inducedseizuresandbrain damage in the tat: differcnt effects ofNMDA- and AMPA rcccptor antago-nists. Pharmacol Toxicol 73:262-268.
Bernard PS, Bennet DA, Pastor G, Yokayarna N, Liebrnenn JM (1985)CGS 9896:
agonist-antagonist benzodiazepine receptor activity revealed by anxiolytic,anticonvu lsantandm uscle relaxation assessment in rodents. J Pharrnacol ExpTher235:98-105.
BernasconiR, lein M, MartinP,ChristenP,HafnerT, ortet C, Schmutz M (1 88)y-Viny GABA : comparisonofneurochemicaland anticonvulsanr effects in mice.
J Neural Transm 7 2 2 13-233.Bigge CF,Wu J-P, h m m e o n d IT, Coughenour LL. Haachin CM (1992)Excitatoryamino acids: 6-phosphonomethyltetrahydro-4-pyrimidinecarboxylic cids andtheir acyclic analogues arecompetitive N-methyl-D-aspartic ac id receptor antago-nists. Bioorg Med Chem Lett 2:207-2 12.
Birse EF, Eaton SA, Jane DE. ones PCS, Porter ECHP, Pook PC-K. Sunter DC,Udvarhelyi PM , Wharton B , Roberts PJ, Salt TIE, Watkins JC (1993) Phenyl-
glycine derivatives as new pharmacological toals for investigating the role of
rnetabotropic glutamate receptors in th e central nervous system. Neuroscience52:48 1 - 4 8 .
Bisaga A, Krzascik P,Jankowska E,Palejko W, ostowski W, anysz W (1993)Effect of glutamate receptor antagonists on N-methyl-D-aspartate and (S)-a-
amino-3-hydroxy-5-methyl4-isoxazolepmpioiccid-induced convuIsanteffects
in mice and rats. Eut J PharmacoE 242:213-220.
BlakePA,Yarnaguchi S,ThurkaufA. RogawskiMA(1992)Anticonwlsant l-phenyl-cycloalkylamines: two analogs with low motor toxicity whenorally administered.Epilcpsia 33:188-1 94.
Blaschkc M, Keller BU, ivosecchi R, HoIImann M, einemann S , Konnerth A
(1993) single amino acid determines the subunit-specific spider toxin block nf
a-amino-3-hydmxy-5-methylis~x~ole-4-proponatkainateceptor channels.Proc Natl Acad Sci USA 9k6528-6532.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 59/81
Epilepsy 251
Bobelis DJ, Ralster RL (1 993) PhamacolagicaI specificity of the discriminative
stirnuluspmperties of2-arnino-4,5-(1,2-cyclohexyl)-7-phosphona-heptanoiccid(NPC 12626), a competitive N-methyl-D-aspartatc receptor antagonist . J
Pharmacol Exp Ther 264:R45-853.Borden LA, DharTGM, Smith KE, Weinshank RL, Bnnchek TA, Gluchowski C (1 994)
Tiagabine, SK & F 89976-A, CI-966, and NNC-7 1 1 arc selective for the cloned
GARA transporter GAT-1. Eur J Pharmacol- Mol Phamacol Sect 259:219-224,Bracklcy PTH, Re11 DR, Choi S-K, Nakanishi K , Ushemood PNR 1993) Sclectivc
antagonism of native and cloned kainate and NMDA receptors by polyamine-containing toxins. J Pharmacol Exp Thcr 266:1573-1580.
Rraestrup C,Nielsen M (1986)Benzodiazcpinc receptor binding invivo
and efficacy.In: Bcnzodiazepine/GABA receptors and chloridc chann els: structural and func-
tional properties (Venter JC, Olsen RW, cds), pp 167-1 84. New York: Liss.Braestrup C, Nielsen EB, Sonnewald, U, Knutsen LJS, Anderscn KE, lansen JA,
Frederiksen K, Andessen PW,Mortenscn A, Suzdak PD (1990) (R)-N-[4,4-
Bis(3-mtthyl-2-thicnyl)but-3-cn-l-yljnipecoticcid binds with high affinity to
the brain y-amfnobutyric acid uptake carrier. J Neurochem 54:639-747.
Carling RW, Leeson PD, Moore KW, Smith JD,Moyes CR, Mawer IM, Thomas S,Chan T, Bakcr R, Foster AC, Grimwood S, Kemp JA. Marshall GR, ricklebankMD, Saywell KL (I 993)3-Nitro-3,4-dihydro-2(1 H)-quinolones. Excitatory amino
acid antagonists acting at glycine-site NMDA and (RS)-a-amino-3-hydmxy-5-methyl-4-isoxazolepropionfc acid receptors. J Mcd Chem 36:3393-3408.
Carter AJ (1992) Glycine antagonists: regulation of the NMDA receptor-channelcomplex by th e strychnine-insensitive glycine site. Drugs Eut 17:595413.
Chapman AG, DiirmallerN,Harrisan BL, Baron BM, Parvez N,Meldmm BS ( 1 945)Anticonvulsant activity of a novel NMD A/glycine siteantagonist, MDL E04,653,against kindled and sound-induced seizures. Eur J Pharmacol 274:13H8.
Chapman AG, Diinniiller N, Parvez N, Harrison EL,Baron BM, Meldrum BS ( 1 993)The anticonvulsant actionofanovelNMDAJglycine site antagonist, MDL 104,653,
following systemic administration to DBA/Z mice or kindled rats. Soc NeurosciAbstr 19:472.
Chapman AG, MeldrumBS 1 993) Excitatory amino acid antagonists and epilepsy.Riochem Soc Trans 21:106110.
Chapman AG, Smith SE,Meldrum BS 199 1)The anticonvulsant effect of the non-N M D A antagonists, N RQ X and G Y K I 52466, in mice. Epilepsy Res 9:92-96.
Cheung 13, Kamp D, Harrts E (1992) An in vitro investigation of the action oflamotrigine on ncurenal voltage-activated sodium channels. Epilepsy Res12:107-112.
Chu P, Shirahata A, Sarnejima K, Saito H , Abe K (1 994) N-(3-Aminopropyl)-cyclo-
hcxylamine blocks facilitation by spemidine of N-methyl-DL-aspartatc-inducedseizure in mice in vivo. Eur J Phamacol 256: 155-1 60.
Coffin V, Cohen-Williams M, Rarnett A (1994) Selective antagonism of the
anticonvulsant effects of felbamate by glycine. Eur J Pharmacol 256:R9,R10.CoulterDA, Hupenard JR , Prince D A 1 989a)Calcium cumcnts in rat thalarnocortical
relay ncuroncs: kinetic propertiesof the transient, low-threshold current. J PhysiolILondS 434:587404.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 60/81
Coulter DA, Huguenard JR, Prince DA (19R9b)Characterization of ethosuximide
reduction o f low-threshold calcium current in thalamic neurons. Ann Neurol25:5X2-593.
Couiter DA, Huguenard JR, Prince DA (1990) Diffesential effects of petit malanticonvulsants and convuisants an thalamic neurones: calcium current reduction.Br J Phamacol 100:80&8O(i.
Coulter DA. Lee CI (1493) Thalamocortical rhythm generation in v i m : extra- andintracellular recordings in mouse thalamocortical slices perfused with low Mg2+medium. Brain Res 631:137-142,
Craig CR (1966) Anticonvulsant activity of steroids: separability of anticonvulsantfrom hormonal cffects. J Pharmacol Exp Ther 153:337-343.
CraigCR, eason JR ( 1968) Anticonvulsant activity of steroids, specificityof stmc-ture. Arch ht Phamacodyn 172:36&372.
Crepe1 V, Kmjevic K, Ben-Ari Y 1 991 ) Glibenclamidedepresses the slowly inacti-vating outward current (I,) in hippocampal neurons. Can J PhysioE Phamacot70:306.307.
Csouchcr MJ, C ollins JF, M e l d m (1982) Anticonvulsant action of excitatory aminoacid antagonists. Science 2 16399-90 1 .
Dana C, Benavides J , Schoemaker H, Scatton B (1991) Pharmacological charactmi-sation and autoradiographic distribution of polyamine-sensitive [3H]Efenprodilbinding sites in the rat brain. Neurosci Lett 125:4548.
Davies J. Evans RH, Herrling PL, Jones AW, Olverman HJ, Pook P, Watkins JC( 1 986)CPP, a new potent and selective NMDA antagonist. Depression of central
neuron responses, affinity for ['HID-APS binding sites on brain membranes and
anticonvulsant activity. Brain Res 382:16%173.
Davies SN. CollingridgeGL
( 1990 ) Quinoxalinediones as excitatory aminoacid antagonists in the vertebrate central nervous system. Int Rev Neurabial32:281-303.
Deacon RMJ, uy AP, Gardiner CR (1 991) Effectsof selected irnidazopyrimidineligands forbenmdiazepinereceptors in rodentmodels of anxiety and behaviouralimpairment. Drug Dev Res 22:32 1-329.
Del PozoE, Ramos M, Baeyens IM (1990)Effects of potassium channel openers on
pentylenetetrazole-induced seizures in mice. Pharmacol Toxicol67: 182-1 84.Deren-Wcselek A, Maj J (1993) Central effects o f SL 82.0715, an antagonist of
polyarnine site of the W D A eceptor campiex, Pol J Pharmacol45:4674R0.
Dc S amG , Dc Sarro A (1992) Anticonvulsant activity of competitive antagonists ofNM DA receptor in gene tically epitepsy-prone rats. Eur J Phamacol215:22 1-229.
De Sarro GB, Dc Sarro A (1993) An tic~nv ulsant ropert ies of non-competitiveantagonists of th e N-methyl-D-aspartate receptor in genetically epilepsy-pronerats: comparison with CPPenc. Neuropharmacology 3235 1-58.
Dolin SJ, Smith MB, Soar J, Morris P3 ( I 992)Does glyciae antagonism underlie the
excitatory effects of methohexitone and propofol? R r J Anacsth 68523-526,
Donevan SD, ones SM , Rogawski MA (1 992) Arcaine blocks N-methyl-D-aspar-tate receptor responses by an open channel mechanism: whole-cell and single-
channel recording studies in cultured hippocampal neurons. Mol Pharmacol
41:727-735.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 61/81
Epilepsy 253
Donevan SD.Ragawski MA (1993) GYKF 52466, a 2.3-benzodiazepine, is a highly
selective, noncompetitiveantagonistofAMPAJkainatereceptosresponses.Neuron10:51-59,
Donevan SD, YamaguchiS,Rogawski M A ( 1 994)Non-N-methyl-D-aspamte recep-tor antagonism by 3-N-substituted 2,3-benzodiazepines: relationship to anti-convu lsant activity. J Pharmacol Exp Thcr 27 I :25-29.
Dragunow M ( 1 986)Adenosine: the brain's natural anticonvulsant?TrendsPhamacolSci 7:128-130.
Dragunow M, Goddard GV (19R4)Adenosinemodulation o f amygdala kindling. Ex pNeurol 84:654465.
Dunwiddie TV (1980) EndogenousIy released adenosine regulates excitability in thein vitru hippocampus. Epilepsia 21:54 1-548.
Dunwiddie TV, Wonh T (1 982) Sedative and anticonvulsant effects of adenosineanalogs in mouse and rat. J Pharmacol Exp Ther 220:70-76.
During MI, Leone P,Davis KE, Kerr D, Sherwin RS (1995)Glucose modulates ratsubstantia nigra C A B A release in vivo via ATP-sensitive potassium channels.J
Clin Invcst 95:2403-2468.During M , Maltson R, SchcycrR, askC, PierceM, MckelvyJ, ThomasV (1992)The
effect of tiagabine hydrochloric acid on extracellular GA BA levcls in the humanhippocampus. EpiEepsia 33(Suppl 3):83.
During MJ, Spencer DD (1942)Adenosine: a potential mediator of seizure arrest andpostictal refractoriness. Ann Neurol 3 2 6 1 8-624.
During MJ, Spencer DD (1993) Extracellular hippocampal glutamate and spontane-ous seizures in the conscious brain. Lancer 34 1: 1607-16 10.
D amt i l l e r N, Craggs M, Meldrum B S (1994)The effect o f the non-NMDA receptor
antagonist GYKE 52466 andNBQX and the competitiveNMDA eceptor antago-nist D-CPPene on thedevelopment of amygdala kindling and onamygd ala-kindledseizures.Epilep sy Res 17: 167-1 74.
h v a l D, oome N, Gauffeny C, Nowicki JP , Scatton B (1992) SL 82.0715, an
NMDA antagonist acting at the polyamine site, does not induce neurotox ic effectsnn rat cortical neuron s. Neurosci Lett 137:193-1 97.Evans JM , Thompson M, Upton N 1992)Benzo- and pyridopyran derivatives having
anxiolytic and anti-conv ulsant activity. W orld Patent Application 92/22293.
Facklam M, Schoch P,Ronetti EP, Jenck F,Martin JR , Moreau JL, Haefely W E
( 1 492a)Relationship between benzodiazepine receptor occupancy and functional
effects in vivo of four ligands o f differing intrinsic efficacies. J PharmacoE ExpTher261:1113-1121.
Facklam M, Schoch P, Waefely WE (I992b) Relationship between benzodiazepinereceptor occupancy and potentiation o f y-aminobutyric acid-stimulated chloride
flux in vitm of four ligands of differing intrinsic efficacies.J PharmacoI Exp Ther261:lIOh-1112.
FaggGE. lpe H-R. Pozza MF, Baud J, Steinmann M, SchmutzM, Pottet C, BaurnannP,Thedinga K. B i t t i ~ e rH, ilgeier H. Heckendom R, Angst C, Rrundish D,
Dingwall JG (1990 )CG P 37849 and CGP 39551: novel and potent comp etitive
N-methyl-D-aspartate receptor antagonists with oral activity. Rr J Phnrrnacol99:791-797.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 62/81
254 Rogawski
Farwell JR, Lee YJ, Hirtz DG, Sulzbacher SI, Elfenberg JH, Nelson KB (1990)
Phenobarbital for febrile s e i z u r e ~ f f e c t s n intelligence and on seimre recur-rence.N Engl J Med 322:36+369.
Faught E,Sachdeo RC, emlcr MP, Chayasirisobhon S, Iragui-Madoz VJ, Ramsay
RE, Sutula TP, Kanner A, Harner RN,Kuzniecky R, Kramcr LD, Karnin M,
Rasenberg A (1993)Fclbamate monotherapy for partial-onset seizures:an active-
control trial. Neurology 43:68R-692.Faure-Hallcy C,Graham D, Arbilla S, Langer SZ 1993) E~p tcss ion nd properties
ofrecombinant a,!3,y2and a,P,y,formsoftheratGABA, receptor.EurJPhamacol
(Mol Pharrnacd Sect) 246:283-287.
Fecly M, RoyEand P, Picardo A, COXA, Gent J-P (1989) Lack o f anticonvulsanttolerancc with RU 3269R and Ro 17 1812. Eur J Pharmacol 164377-380.
Ferkany JW , Hamilton GS, PatchRJ, Huang 2, Borosky SA, Rednar DL, JonesRE,Zubrowski R, Willetts J, Karbon EW (1993) Pharmacological profile of NPC17742 [2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoiccid], apotent, selective and competitive N-methyl-D-aspartate receptor antagonist. J
Pharmacol Exp Thcr 264:256-264.Ferkany JW , Kyle DJ, Willcts J, Rzeszotarski WJ, urewska ME, Ellcnberger SR,
Jones SM, Sacaan AI, Snell LD, Borosky S, Jones BE, JohnsonKM, Balster RL,Burchctt K, KawasakiK, Hoch DB, Dingledine R (1989) Pharmacological profile
of NPC 12626, a novel, competitive N-methyl-D-aspartatc receptor antagonist. JPharmacoE Exp Thes 250:1O&109.
Fmaguti F, avanni P, Eistetter H, alvagnoC, RattiE,Trist DG (1994)Competitiveantagonism by phenylgIycinederivatives t type f metabotropic glutamate recep-
tors. Mol Cell Neurosci 5:269-276.
EerrendelliJA,
Holland KD. McKeon AC, Covey DF (1989) Comparison of theanticanvulsant activities of ethosuximide, valproate, and a new anticonvulsant,thiobutyrolactone. Epilepsy 30:6 17422 .
Ferrendelli JA , McKeon AC, Xu K, Covey DF (1993) Comparison of th e anti-convulsant effects of a-ethy1,a-methyl-thiobutymlactbncnd clonazeparn after
chronic treatment, Epilepsia 34tSuppl 6):llR.Mench-Mullen JMH, arker JL, Rogawski M A (1993) Calcium current block by
(-)-pentobarbital in acu tely isolated hippocampal CAI neurons: comparison with
effects on GABA-activated CI- current. J Neurosci 13:32 1 1-322 1.
Fink-Jensen A, Suzdak PD, wedberg MDB, Judge ME, ansen L, NieIsen PG
(1992) The y-aminobutyric acid ( G A B A ) u p t a k e inhibi tor , t iagabine,increase s extracellular brain levels of GABA in awake rats. Eur J Pharmacol
220:197-201,
FischerW, odewei R, atzingerG 11992)Anticonvulsant and sodium channel block-ing effects of ralitoline in different screening models. Naunyn Schmiedeberg'sArch Phamacol346:442-452.
Fix AS, Horn JW, Wightman KA, Johnson CA, Long GG, Storts RW, Farber N,
Wozniak DF, Olncy J W (1993) Neuronal vacuolization and necrosis induced bythe noncompetit ive hr-methyl-D-aspartale (NMDA) antagonist MK[+)XOI
(dizocilpinc maleare): a light and clectron microscopic evaluation of the ra t
rctrosplenial cortex. Exp Neurol 123:20&2 15.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 63/81
Epilepsy 255
Friedman LK, PellegrinE-GiampEetro DE, Sperber EF, Bennett MVL, Moshe SL.
Zukin RS (1994) Kainatc-induced status epilepticus alters glutamate and GARA,receptor gene expression in adult rat hippocampus:an i n situ hybridization study.
J Ncurosci 14:2697-2707.
Gale K (1985 ) Mcchanisms of seizure control mediated by y-aminobutyric acid: roIeof the ~u bstan tia igra. Fed Proc 44:241k242.4 ,
GaleK (1992) G A R A and epilepsy: basicconcep ts froimpreclinicalmsearch.Epilepsin33(S~ppl ):53-S 12.
Gandolfo C i , Gottesmann C, Bidard J-N, Lnzdunski M (1989a) K + channels openersprevcnt epilepsy tnduced by th e bce venom peptide MCD. ur J Pharmacol
159:329,330.Gandolfo G, omettino S, Gottesmann C, van Luijtclaar G, Coenen A, Bidard J-N,Lazdunski M ( 19H9b)K+channel openers decrcasc seizurcs En genetically epilep-tic rats. Eur J Pharmacol 167:18 1-1 83.
Gardner CR (1988) Functional in vivo correlatesof the benzodiazepine agonist-inverseagonist continuum. Prog Neurobiol 3 1 :425--476.
Garreau M, Zivkovic B, Morselli PL ( 1992) Alpidcm from pharmacology to clinic.Clfn Neuropham I S(Suppl 1, Pt A):407A,408Am
Glaun SR,Miller RJ (1994)Acu te regulation of synaptic transmission by metabo-
tropic glutamate receptors. En: Thc mctabotropic glutamate receptors (Conn PJ,
Pate1 J, eds), pp 147-172. Totowa, NJ: Humana.Gloor P (1968) Generalized cortico-reticular epilepsies. S om e conside rations on the
pathophysiology of generalized bilaterally synchronousspike and wavedischarges.Epilepsia 9:24%263.
Gloor P 1 984) Iectrophysiology ofgeneralized epilepsy. In: Electrophysiofogyofepilepsy (Schwartzkroin PA,Wheal HV, eds), pp 109-136, London: Academic.
Gold LH, Balster RL ( 1993)Effects ofWMDA receptor antagon ists in squirrel mon-keys trained lo discriminate the competitive N M D A receptor antagonist NPC12626 from saline. Eur J Phamacol23U:2g5-292.
G6tz E, Feucrstein TI,Lais
A, Meyer DK (1993)Effects of gabapentin on releaseof y-aminobutyric acid from slices of rat neostriatum. Armeimittelforschung43:636-638.
Grant KA, Snell LD, Rogawski MA, Thurkauf A. Tabakoff B (1992)Comparison ofthe effects of th e uncompetitive N-methyl-D-aspartate antagonist (+)-5-amino-carbonyl-lo,] 1-dihydro-SH-dibenzob,d]cyclohepten-510-imineADCI) with its
structural analogsdizocilpine (MK-80) and carbarnazepine on ethanol withdrawal
seizures. J Phamacol Exper Ther 260: 1017-1 022.Grant KA, Valverius P.Audspith M. TabakoffB (1990)Ethanol withdrawal seizures
and the NMDA receptor comptex. Eur J Pharmacol 176:289-296.
Greene RW , Haas HL (1991)T h e electrophysiology of adenosine in the mammaliancentral nervous system. Prog Neurobiol36:329-341.
Haefcly W. Martin JR , Schoch P (1990)Novel anx iolytics that act as partial agonists
at benzodiazepine receptors. Trends Pharmacol Sci 1 1:452-456.
Haigh JRM, Feely M (1988) R o 16-6028, a benzodiazepine receptor partial ago-
nist , does not exhibit anticonvulsant tolerance in mice. E u r J P h a m a c o l147:283-285.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 64/81
HalesTG, amben JJ ( 1 991)The actions ofpropo fol on inhibitory arninoacid recep-tors of bovine adrenomedullary ehromaffin cells and rodent central neurones.BrJ Phannacol 104:619-628.
Hales TG, Lambert JJ (1992)Modulation of GABA, and glycine receptors bychlormethiazole. Eur J Pharmacol2 10:239-246.
Hamilton GS , Huang 2, atch RJ, Narayanan BA, Eerkany JW (1993) Enzymatic
asymfnctric synthesis of (2R,4S5S)-2-amino-4,5-(1,2-cyclohexyl)-7-phosphono-hcptanoic acid, a potcnt, selectivennd competitive NMDA antagonist. Rio og Med
Chem Lett 327-32.Hamsworth WL,Wolf HH, winyard EA, White HS (1993) Felbamaremodulates
glycine reccptw function. Epilepsia 34(Suppl2):92.Harrison NL, Simmonds MA (1 984) Modulation of the GABA receptor complex by
a steroid anaesthetic. Brain Res 328287-292.HasanZA, Hasan MM, al-HaderAA, Takrouri MS 1 992) The effect afpmpofol and
thiapentone on pentylcnetetrazol seizure threshold in the rat. Middle East J
Anesthesiol 1 1 359-367.
HasanFA,WolleyDE 1994) omparisonof the effecls of propofoland thiopental on thepattern of maximal electroshock seizures in the rat. Pham acol Toxisol 745053.
Hausser MA, De Weille JR, Lazdunski M (1991 ) Activation by crornakalim of pre-
and post-synaptic ATP-sensitiveK'channelsin ubsiantianigra.Biochem Biophys
Res Commun 174:909-914.HayakawaT,Hamada Y, M a i h m T,Hattori H, MikawaH ( 1 994) Phenytoin reduces
neonatal hypox ic-ischemic brain damage in rats. Life Sci 54:387-392.
Hayashi Y, Hattori Y , Moriwaki A, Lu Y-F, Hori Y (1943) Increases in brainpolyarnine concentrations in chemical kindling and single convulsion induced by
pentylenetetrazol in rats. Neurosci Lett149:6346.
Hayashi Y, Hattori Y, Moriwaki A, Saeki K, Hori Y (1989) Changes in p l y m i n econcentrations in amygdaloid-kindled rats. J Neurochem 53;98&988.
Herlitre S, Raditsch M, RuppersbergJP, Jahn W, Monyer H, Schoepfer R, WitzemannV (1993) ArgEotoxin de tects molecular d ifferences in AMPA receptor channels.Neuron 10:1 131-1 140.
Hewett CL, SavageDS, ewis JJ, Sugme MF (1964) Anticonvulsant and interneu-
mnal blocking activity of some synthetic amino-steroids. 3 Pharm Pharmacol
16:765-767.
HBgskilde S, Wagner J, Carl P, Anker N, Angelo WR, Snrensen MB (1988)
Anticonvulsive properties o fpregnanolone emulsion compared with althesin andthiopentone in mice. Br J Anaesth 61:462467.
Holland KD, ovley MG, Covey DE, errendelIi JA (1993) Alkyl-substi tutedy-hutyrolactones ac tat a distinct sireallosterically l in k ed ~o th c BPSlpjcrotoxininsiteon the GABA, receptor complex. Brain Res 61 5:178-1.74.
Holland KD, Ferrendelli JA, Covey DF, Rothrnan SM (1990) Physiological regula-tion of the picrotoxin receptor y-butyrolactones and y-thiobutyrolactones in cul-tured hippocampal neurons. Neurosci 10: 1 7 l + I 727.
Holland KD, McKeon AC, Canney DJ, Covey DF, Ferrendelli SA (1992) Relativeanticanvulsant effects ofGABA-mimetic andGABA modulatory agents. Epilepsia333981-986.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 65/81
Epilepsy 257
Hollmsnn M, Boulter J, MaronC. Beasley L, SullivanJ.PechtG, einemannS ( 1 993)
Zinc potentiates agonist-induced currents at certain splice variants of the NMD Areceptor. Neuron 10:943-954,
Hollmann M, Wartley M, Heinemam S (1941) a2+ ermeability of KA-AMPA-gated glutamate receptor channels depends on subunit composition. Science
252:R5 1-853.
Honori: T,Davies SN,Drejer J, Fletcher EJ, Jacobsen P,Lodgc D, Nidsen FE (1 988)
Quinoxalinediones: potent competitive non-NMDA glutamate receptor antago-
nists. Science 241 701-703.
Honmou 0, yelese A, Kocsis JD (1994) The novel anticonvulsant gabapentin
enhances promoted release of GABA in hippocampus. Soc N eurasci Abst r20: 1640.
Home AL, Hadingham KL, Macaulay AJ, Whiting P,Kemp JA (1992) The pharma-cology of rccombinant GABA, receptors containing bovine a,,,, , sub-unitsstably transfected into mousc fibroblast L-cells. Br S Pharmacol 107:732-737,
Hosford D A, Clark S,Cao2,Wilson WA Jr, Lin F,Morrisett RA, Huh A (1992)Thc
role of GABA, receptor activation in absence seizures o f lethargic ( I h / l h ) mice.
Science 257:398-401.
Huettner JE (1991) Competitive antagonism of glycine at the N-methyl-D-aspartate( NM DA) receptor. Biochem Pharmacot 4 1 :9-16.
Huettncr JE, Bean BP (1988) Block ofN-methyl-D-aspartate-activated urrent by th eanticonvulsant MK-801: selective binding to open channels. Proc Natl Acad Sci
USA 85:1307-13 11.Huguenard JR , McCormick DA (1992) Simulationof th e currents involved in rhyth-
mic oscillations in thalamic relay neurons. J Neurophysisl68: 1373-1 383.HuguenardJR, Prince DA (1992a) Multiple sitesoTactionofsuccinimides and related
anticonvulsants. Epilepsia 33(S upp l3):30.Huguenard JR,Prince DA (1 992b)A novelT-type current underlies prolonged Ca2+-
dependent burst firing in GABAergic neurons of rat thalamic reticular nucleus. J
Neurosci 123804-3817.Huguenard JR Prince DA (1994) lntrathalamic rhythmicity studiedin virro:nominalT-current modulation causes robust antioscillatoryeffects. JNeurosci 14:548%5502.
Humc RI, Dingledine R, einemann SF (1991) Identification af a site in glutamatereceptor subun its that controls calcium permeability. Science 253:1022-1 03 1.
Hutchison AJ, Williams M, Angst C, De Jesus R,Blanchard L, JacksonRH, Wilusz
EJ, Murphy DE, Bernard PS, Schneider J, Campbell T, GuidaW, SillsM A ( 1 989 )
4-(Phosphonoalky 1) - and 4-(phosphonoalkeny I)-2-piperidinecarboxy c acids:
synthesis. activity at N-methyl-D-aspartic acid receptors, and anticonvulsant
activity. J Med Chem 3 2 2 171-21 78 .
Irn HK, ImWR, amiitan RJ, CarterDR, onvoightlander PF (1993 ) Potentiation ofy-aminobutyric acid-induced chloride currents by various benzadiazepine si te
agon ists with the a,y,, B2y Iand a,y, subtypes of cloned y-arninobutyric ac id type
A receptors. Mol Pharmacol44:R6Gt(70.
Jackson HC, Byrholm I, Klitgaard H (1994)Effect of adenosine A, receptoragonists
on the seim res induccd by thc potassium channel blocker Caminopyndinc inmice. Brit J Pharmacd 1 Z Proc Su l :614 .
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 66/81
258 Rogawski
JacksonHC, Klitgaard N, cheideler MA (1994) Behavioral effectsafN- and P-type
calcium channel blockers in mice. Soc Neurosci A bstr 3273 .Jahnsen H, Llinas R ( 19X4a) Electrophysiological properties of guinea-pig thalamic
neumnes: an in virro study. J Physiol (Lond) 349:205-226.
Jahnsen W, l inls R (1984b)onic basis for the clectroresponsiveness and oscilla-tory properties of guinea-pig thatamic neurons in vitro. J Physiol (Lond)
349:227-247.Jasper HH 1 99 I ) Current evaluation of the concepts of ccntrencgrhalic and cortico-
reticular seizures. Electroenceph CIin Neurophysiol 7X:2-11.Jenck F, Moscau E L , Ronetti EP, Martin JR , HaefeFy W (1992) Ro 19-8022, a
nonbenzodiazepine par t ia l agonis t at benzodiazepine receptors: neuro-
pharrnacologicaI profile of a potential anxiolytic. J Pharmacol Exp Ther262: 1 12 1-1 127.
Jensen LH, Marescaux C, Vergnes M, Micheletti G, PetersenEN 1984)Antiepilepticaction of the P-carboline ZK 91296 in a genetic petit ma! model in rats. Eur J
Pharmacol 102521-524.
Jahansen TH, rejer J, WStjen E, Nielsen EO 1993) A novel non-NMDA receptorantagonist shows selective displacement of low-affinity ['Hjkainatc binding. Enr
J Pharmacol246: 195-204.Johnson DN, White HS, SwinyardEA, Albertson TE, Kilpatrick BF (1991) AHR-
12245: a potential anti-absence drug. Epilepsy Res 8:64-70.Johnson JW, Ascher P (1987) GIycine potentiates the NM DA response in euItured
mouse brain neurons. Nature 325:52%53 1.
Jones MG, Bond A, Lodge D (1992)Antagonism o f excitatory amino acid-evokedresponseof rat spinat ncurones in vivo by 2,3-benzodiazepines GYKI 52466 andGYKl53655 . Br J Pharmacol 107(Proc Suppl): 243P.
Jones SM, Rogawski MA (1992) The anticonvulsant (+)-5-aminocarbonyl-10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5,lO-imineADCI) selectively blocksNMDA-activated current in cultured rat hippocampal neurons: kinetic analysisand comparison with dizocilpine. Mol Neuropharmacol 2:303-3 10.
Katchman AN. Hershkowitz N (1463) Adenosine antagonists prevent hypoxia-induced depression o f excitatory but not inhibitory synaptic currents.NeurosciLett 159:123-126.
KawajiriS,Dingledine R (1993)Multiple structural determinants ofvoltage-depen-dent magnesium block in recombinant NMDA receptors. Neuropharmacology
32~1203-1211.Kelly KM, Gross KA, Macdonald RL 1990) VaIproic acid selecrively reduces the
low-threshold (T) calcium current inrat nodose neurons.Neurosci Lett I 116:232-238.
Kiskin NI, Chizhmakov TV, Tsyndrenko AYa, Ksishtal OA, Tegtmeier F (1993)
R56865 arid flunarizineasNa+-channelblockers in isolatedPurkinjeneuronsof rat
cerebellum. Neuroscience 54575-585.
KlecknerNW, DingledineR (1 9X8)Requirement for glycine in activation ofNMDA-
receptors expressed in Xehopus oocytes. Science 2412335-837.Klitgaard H, Jackson HC (1993) Ccntral administration of L-amino-3-phosphoro-
propionate (L-AP3) inhibits nudiogenic seizures in DBA/2 mice. Funct Ncurol
4(Suppl):28.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 67/81
Epilepsy 259
Knoflach F,Drescher U, Scheurer L, Malherbe P,Mohler H (1 993) Ful l and partial
agonism displayed by benzodiazepine receptor l igands a t recombinant y-a~ninobutyric cid, receptor subtypes. J Pharmacol Exp Ther 266;385-39 .
Kocsis JD, Honmou 0 1994) G~bapent inncreases GARA-induced depalarizationin rat nconataI optic nerve. Ncurosci Lett 169:181-1 84.
Kock W , Colpacrt FC (1990)Selective blockade of N-methyl-D-aspartate (NMDA)-induced convuIsions by NMDA antagonists and putative glycinc antagonists:
rclationship with phencyclidine-Iike behavioral effccts. J Phnrmacol Exp Ther252349-357.
KShr G, Hcinemann U (1990) Anticonvulsant effects of tetronic acid d erivatives on
picrotoxin induced epilcptifom activity in rat hippocampal slices. Neurosci Lctt112:43-47.Kokate TG, Cohcn A, Karp E, Rogawski MA (1995a) Neuroactivc steroids protect
against pilocarpine- and kainicacid-induced limbic scizurcs and status epilepticusin mice. Soc Neurosci Abst, in press.
Kakate TG, Rogawski M A (1994)Neurosteraideffects on experimental limbic status
epilepticus induced by kainic acid in mice. Epilepsia 35(Suppl 8):68.
Kokate TG, Svennson BE, Rogawski M A (1994) Anticonvulsant activity ofneurosteroids: correlation with y-aminobutyric acid-evoked chloride currentpotcntia~ion. Ph am aco l Exp Ther 270: 1223-1229.
Kokate TG, Yamaguchi S, Rogawski M A (1995b) Lack of tolerance to theanticonvulsant activiiy o ft he neuroactive steroid pregnanolone with chronic dos-
ing in mice. Epilepsia, in press.Kostyuk PC;,Molokanova EA, PronchukNF, Savchenko AN, Verkhratsky AN (1 992)
Different action of ethosuximide on low- and high-threshold calcium currents in
rat sensory neurons.Neuroscience 51755-75 8.Krystal JH, Karper LP, SeibyI JP , Freeman GK, Delaney R, Bremner JD , Heninger
GR, Bowers ME r. Charney DS (1 994) Subanesthetic effects of the noncornpeti-tive N M D A antagon ist, ketamine, in humans. Psychotomimetic, perceptual, cog-
nitive, and neuroendocrine responses. Arch Gen Psychiatry 5 1: 199-2 14.KuFagowski 53, Baker R. Curtis NR, Leeson PD, Mawer IM , Moseley AM, RidgillMP, owley M, Stansfield I, Foster AC, Grimwood S,Hill RG, Kemp JA, Marshall
GR, Saywell KL. Tricklebank MD (1994) 3'-(Arylmethy1)- and 3'-(aryloxy)-3-phenyl-4-hydroxyquinolin-2(1H)-ones: orally active antagonists of the glycfne
site on the NMDA receptor. J Med Chem 37;1402-1405.
Kulak W , SobaniecW(1994) Anliconwlsanteffects ofloreclezole, anew antiepilep ticdrug, and sodium valproate in rats with electrically-induced seizures. Neuro-sciences 20:191-1 95.
Kua CC. Rean BP ( 1 994)Na' channels must deactivate to recover fiom inactivation.
Neuron 12:81%829.Lang DG, W a n g CM, Cooper BR (1 993) Lamotrigine, phenytoin and catbamazepine
interactions on the sodium current present in N4TG 1 mouse neurohlastorna cells.
J Pharmacol Exp Ther 266:82%335.Leach M J, Marden CM, Miller AA ( 1 986) PharmacoIogical studies on larnotrigine,
a novel potcntiai antiepileptic drug: II. Neurochemicol studies on the mechanismof action. Enilensia 27 :49W97 .
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 68/81
260 Rogawski
Leander D, Ornstein PL (1990) The behavioral pharmacology of LY233536 andLY2746 14: two novel, selective, competitive NMDA antagonists. Soc NeurosciAbstr 16:858.
Lee KS, chubefi P, Heinemann U (1984) The anticonvulsive action ofadenas ine: apstsynaptic,dendrEtic action by apossiblc endogenous anticonvulsant. BrainRes
321:160-164.
Lees G, Leach MI (1993) Studies on the mechanism of action of the novelanticonvulsant lamotrigine (Larnictal) using primary neuroglial cultures from ratcortex. Brain Res 612:19@-199.
Leeson PD,Williams BJ, Baker R, Ladduwahetty T,Moore KW, Rawley M 1990)
Effects of five-membered ring conformation on b ioreceptor recognition: identifi-cation of3R-amino- 1-hydmxy-4R-methylpyrrolidin-2-one(L-687,4I4)sa potentglycineJN-methyl-0-aspartateeceptor antagonist, J Chcm Soc, Chcrn Commun22: 1578-1 580.
Leeson PD, Williams BJ, Rowley M, Moore KW, Baker R Kemp JA, Priestley T,FosterAC, Donald AE (1993) Derivatives of 1-hydroxy-3-aminoppolidin-2-one
(HA-966). Partial agonists at the glycine siteof theNMDA receptor. Bioorg MedChem Lett 3:71-76.
LegendreP,Westbrook GL (1 991) Ifenprodit blocks N-methyl-D-aspartateeceptorsby a two-component mechanism. Mol Pharrnacol40:289-298.
Lehmann J, Hutchison AJ. McPherson SE, Mondadori C, Schmutz M, Sinton CM,Tsai C, Murphy DE, teel DI,Williams M, Cheney DL, Wood PL 198R) CGS19755, a selective and competitive N-methyl-D-aspartate-type excitatory amino
acid receptor antagonist. J Pharmacol Exp Ther 24655-75.Lehmann J , SchneiderJ, McPherson S, Murphy DE, Bernard P, Tsai C, Bennett DA,
PastoreG. teeleDJ,Boehrn C, CheneyDL, Liebmann JM , Williams M. Wood PI,( 1 987)CPP, selective N-methyl-D-aspartate (NMDA)-typereceptor antagonist:characterization in vipo and i n vivo. J Phamacol Exp Ther 240:737-746.
Lewin E, Bleck V (198 1) Electroshock seizures in mice: effecton brain adenosine andits metabolites. Epilepaia 22:557-581.
Liljequist S ( 1 991)Thecompetitive NM DA receptorantagonist, CGP3955 , inhibitsethanol withdrawal seizures. Eur J Pharmacol 192:197,198.
Liu A, Vergnes M, Depaulis A, Marescaux C ( I 992) Invotvement of intrathalamicGARA, ncurottansmission in the control of absence seizures in the rat. Neuro-science 48:R'F-93.
L6scher W 2993)Abecamil shows educed tolerance development and dependencepotential in comparison to diazepam: animal studies. Psychopharmacol Ser
11~96-112.
G s c h c r W, HGnack D I 991a) Antieonvulsant and behavioral effects of two novelcompetitiveN-methyl-D-aspartic acid receptor antagonists, CGP 37849and CGP39551, in the kindling model of epilepsy, Comparison with MK-801 andcarbamazepine. J PharmacoF Exp Ther 256;432-440.
LhscherW, HonackD (199 I b) The novelcompetitiveN-methyl-D-aspartateNMDA)antagonistC GP 3784 9 preferentially induces phencyclidine-like behavioral effectsin kindled rats: attenuation by manipulation ofdopaminc. alpha-1 and seratonin,,
receptors. J Pharmacol Exp Ther 257; 1146-1 153.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
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Epi l epsy
Loscher W , H6nack D.Scherkl R,Rashem A, Frcy H-H ( 1 990) hamacokinetics,
anticonvufsant efficacy and adverse effects of th c P-carbotfne abecarnil, a novclligand for bcnzodiazepine receptors, after acute and chronic administration in
dogs. J Pharmacol Exp Thcr 2 5 5 3 4 1-548.LoschcsW, Gnack, Taylor CP (1991a)Gabapentin increases aminooxyacetic acid-
induced GABA accumulation in several regions of rat brain. Neurosci Lett128:1 5 6 1 4.
LBscher W ,Rundfeldt C, Rijnack D(1991 b)Tolerancc to anticonvulsant eff ectsof the
partial bcnzodiazepine eceptor agonist abecarnil in kindled rats involves learning.Eur J Phnmacol202:303-3 10.
LBscherW , Rundfcldt C, Hsnack D ( 1 993)Low doses ofNDMA rcceptorantagonistssynergistically increasethe anticonvulsant effect ofthc AMPA receptor antagonistNBQX in thc kindling model of epilepsy. Eur J Neurosci 5: 1545-1 550.
Lytton W W , Scjnowski TJ (1992) Computer model of ethosuximidc's effcci on athalamic neuron. Ann Ncurol32: 131-139.
MacDonald JF, Bartlctt M C , M ody I, Pahapill P,Reynolds JN, Salter M W ,
Schneideman JH, Penncfather PS 1991)Actions ofkctaminc, phencyclidine and
MK-80 1 on NMDA receptor currents n cultured mouse hippocampal neurones. 5Physiol (Lond) 432:483-508.
Macdonald RL, Rogers CJ, Twyrnan RE (1989) Barbiturate regulation of kinetic
properties of the GABA, receptor channel of mouse spinal ncurones in cutture. JPhysiol (Lond) 4 17:483--500.
MaitreM, ChesielskiL,Lehmann A, Kernpf E, Mandel P (1974) rotective effectof deno-sine and nicotinamide against audiogenicseizure. Biochem Phamcol23:2807-2816.
Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM 1 986) Steroid hor-
moncmetabolites are barbiturate-like modulators o f thc GAB A receptor. Science232:1004-1007.
Makela JP, livanainen M, Pieninkeminen IF,Waltimo 0, ahdensuu M ( 1 993) Sei-zures associated with propofol anesthesia. Epilepsia 34:832-g35.
Manzoni DJ,Manabe T, Nicoll 13A(1994)
Release of adenosine by activation sfN M D A receptors in the hippocampus. Science 265:209E-2 I0 1.
Marangos PJ, Loftus T,Wiesner J, Lowe T,Rossi E, Browne CE, GruberHE (1990)Adenosinergic modulation of homocysteine-induced seizures in mice. Epilepsia31:239-246.
Marescaux C, Vergnes M, Bernasconi R 1992a) GABA, receptorantagonists; poten-
tial new anti-absence drugs. J Neural Transm 35(Suppl):179-I 88.
MarescauxC, ergnes M, Depaulis A (1992b) enetic absence epilepsy in rats fromStrashurg-A review. J Neural Tmnsm 35(SuppZ):37-69.
Martin JR, PieriL, SchaffnerR, urkard WP, Cumin R, aefelyWE (1 988) Ro 16-6028:
a novel anxiolytic acting as a partial agonist at the benzodiazepine receptor.Pharmacopsychiatry 2 1 3360-362.
Martin PJ,Millac PAH (1993) Vigabatrin: a three year clinical analysis. Seizure
2:137-140.
Mattia D, agao T, Rogawski MA, Avoli M (1994) Potassium channel activatorscounteractanoxic hyperexcitability but not 4-aminopyridine-induced epileptiforrnactiv it in the ra t hi ~ocam al lice. Neurotlharmocolonv 33: 1512-1 522.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 70/81
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
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http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 72/81
Peduto VA, Concas A, Santoro G, Biggio G,Gessa GL (1991) Biochemical andelectrophysiologic evidence that propofol enhances GABAergic transmission in
the rat brain. Anesthesiology 75: 1QOk1009.Penry JK , Porter RJ, Dreifuss FE (1975) Simultaneous recording ofabsence seizures
with videotape and electroencephalography. A studyof374 scizurcs in 4R patients.Brain 9R:427-440.
PerraultG,Morel E, Sangcr DJ, Zivkovic8 1993) Repeated trcatrnent with alpidem,a new anxiolytic, does not induce toEerance or physical dependence. Neuro-pharmacology 32:855463.
Petersen EN ( I 991) Selective protection by adenosine reccptor agonists againstDMCM-induced seizures. Eur J Phannacol 195:261-265.
Pcterscn EN, Jcnsen LH , Drejer J, HonorcT (1986) New perspectives in benzodiaz-epine receptor pharmacology. Pharmacopsychiatry 1 9 : 4 4 .
Petenen EN, jensen LH, Honorc T, Rracstnrp C, Kehr W, Stephens DN, Wachtel H,Scidelrnan D, Schrnimhen R 1984)ZK 1296, a partial agonist at benzodiazepinereceptors. P sychoph amaco logy 83:240-248.
Peterson SL (1989) Antjconvulsant profile of an anesthetic steroid. Neuro-pharmacology 28:877-R79.
Politi DMT, ogawski MA (1991) Glyburide-sensitive K* channels in cultured rat
hippocampal neurons: activation by cromakalim and energy depleting conditions.Mol PhamacoE 40:308-3 15.
Politi DM, Werkman TR,RogawskiMA (1 993)Benzopyranpotassium channel open-as inhibit voltage-activated outward currents in rat hippocampal neurons. Soc
Neurosci Abstr 19:708.
Popoli P,Pezzola A, Sagratella S, Zeng YC, Scotti de CarolisA (1991) Cromakalim(BRL 34915) counteracts the epileptiforrn activity elicitcd by diltiazem andverapamil in rats. Br J Phamacol 104:907-9 13.
Porter RHP, Greenamyre JT (1995) Regional variations in the pharmacology of
NMDA receptor channel blockers: implications for therapeutic potential, J
Neurochem 645 4-623.Pribilla I, Neuhaus R, Huba R, WillmannM, urnerJD, tephensDN, Schneider HH
(1993) Abecarnil is a fi ll agonist at some, and a partial agonist at other recombi-
nant GABA, receptor subtypes. Psychopharmacol Ser 1 1 :5&41.PriestleyT, Woodruff GN, Kemp JA (1989) Antagonism o f responses to excitatory
amino acids on rat cortical neurones by the spider toxin, argiotoxin,,,. Br J
Pharmacol97:1315-1 323.Prince HK, Conn PJ, Blackstone CD,Huganir RL, Levey A I 1994)Down-regu-
lation of AMPA receptor subunit GluM in amygdaloid kindling. J Neurochem
64:462465.Proctor WR, DunwiddieW (1987) Pre- and postsynaptic actions of adenosine in th e
in vitro hippocampus. Brain Res426:187-190.Pullan LM, Britt M, Chapdelaine MJ, Keith RA, LaMonte D, angano TJ, Patel J,
Powel RJ, Stumpo RJ, Warwick PJ, Zinkand WC, SaIama A1 (1990) Stereo-
selectivity fo r the (R)-enantiomer of HA-966 (1-hydroxy-3-aminopyrrolidone-2)at the glycinc site en the N-methyl-D-aspartate rccqtor complex. J Neurochem
55:1346-1351.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 73/81
Epilepsy 265
Ragsdale D, Gant DE, Anis NA. Eldefrawi AT, Wdefrawi ME, Konno K, Miledi R
( I 989) nhibition of rat brain glutamate receptors by philanthotoxin. J PharmacolExp Ther 25 1 :1 5 6 1 3.
Ragsdale D S, Scheuer T, Catteratl W A (199 1) Frequency and voltage-dependent
inhibition of type TIA Na' channels, expressed in a mammalian cell line, bylocal anesthetic, antiarrhythmic, and anticonvulsant drugs. Mol Pharmacol40:7 5 6 7 6 5 .
Ransom RW, Stec NL (1988)Cooperative modulation of rH]MK-801 binding to the
N-methyl-D-aspartate receptor-ion channel complex by L-glutamate,glycinc, and
polyarnines. J fu'curochem 5 1 :830-836.
Reckling JC, Jahnsen H, Laurscn A M (1990) The effect of two lipophilic y-amino-hutysic acid uptake blockers in CA I of the rat hippocampal slice. Br J Pharmacol99: 103-1 06 .
Reddy NL, DelyD, um l GJ, Goldin SM, Hu L-Y, ubbaraoK (1 994) Developmentof a scries of novel N,N'-diatylguanidines as potent glutamate rcleasc blockers.Soc Neurosci A bstr 20:70 .
Remy C, Beaumont I) 1989) Efficacy and safety o f vigabatrin in the long-terntreatrncnt of refractory cpilepsy. Br J Clin Phamacol27(Suppl 1):125s-129s.
Rentmccstcr TW, Hulsrnan JA (1992) Loreclezole monotherapy in patients withpartial seizures. Epilepsy Res 1 1:14 -1 45.
Reynolds EH (1992) y-Vinyl GABA (vigabatrin): clinical experience in adult andadolescent patients with intractable epilepsy. Epilepsia 33(Suppl 5):S30S35.
Rho JM, Donevan SD, Rogawski MA (1994a) Effects of the dicarbamates Eelbarnate
and meprobamate on CiABA-activated CIL currents in cultured rat hippocampalneurons. NeuroCogy 44(Suppl2):A237.
Rho JM, Donevan SD, ogawski M A ( 1 994b) Direct activation ofGABA, receptorsby barbiturates: whole-cell and single channel analys is in cultured rathippocampa[neurons. Sac Neurosci Abstr 20:498.
Rha JM. Donevan SD, Rogawski MA ( 1 994~ )Mechanism of action of th e anti-
convulsant felbarnate: effects on N-methyl-D-aspartate and y-arninobutyric acid,receptors. Ann Ncurol 25:22%234.
Rho JM , Donevan SD, Subrarnaniarn S,Rogawski M A ( I 9 9 4 3 Mechanism ofactionof the anticonvulsant felbamate--opposing effects on N-methyl-D-aspartate andy-aminobutyric acid, receptors. Reply. Ann Neurol36:677,678.
Robertson DW, Steinberg MI (1990)Potassium channel modulators: scientificappli-
cations and therap eut~ c romise. J Med Chem 33: 529-1 541.Rock DM, acdonald RL (19921 The polyarnine spermine has multiple actions on
N-methyl-D-aspartate receptor single-channel currents in cultured cortical neu-rons. Mol Pharmacol41:83-88.
Rock DM, McLean MJ, Macdonald RL, Catterall WA, TayIar CP (1991) Ralitoline(CI-946) and Cl-953 block sustained repetitive sodium action potentials in cul-tured mouse spinal COT^ neurons and displace batrachotoxinin A 20-alpha-ben-
zoate binding in vitro. Epilepsy Res 8:197-203.Rodgers-Neame NT, Covey DF, Hu Y, Isenberg KE, Zorumski CF (I 992) Effectsof
a benz[e]indene on y-aminobutyric acid-gated chloride curren ts in cultured post-
natal rat hi ocam~a l eurons. Mol Pharmacol42:952-957.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 74/81
Rogawski
Rodriguez-Paz JM, nantharam V, rcistman SN 1 995) Block of the N-methyl-D-aspnrtste reccptor by phencyclidine-like drugs is influenced by alternative splic-ing. Neurnsci Cctt 190:147-1 50.
Rognwski M A (1992)ThcNMDA receptor,NMDAantagonistsand epilepsytherapy.h tatus rcport, Dmgs 44979-292.
Rogawski M A (1993) Therapeutic potential of excitatory amino acid antagonists:
channel blockers and 2,3-bcnzodinzcpines. Trends Pharmacol Sci F4:325-33 E .Rogawski M A (1995)Excitatory amino acids and seizures. In : CN S neurotransmitters
and neurornodulators, Vol. 2 glutamate (Stonc TW, ed), pp 219-237. RocnRaton, FL: CRC.
Rogawski MA , Porter RJ (1 990)Antiepileptic drugs: pharmacological m echanisms
and cIinicaE efficacy with consideration o f promising developmental stagc com-pounds. Pharmacol Rev 42:223-286.
Rogawski MA, Thurkauf A, Rice KC, Jacobson AE, ffrench-Mullen JMA 1988)
Anticonvulsant activity of phencyclidine analogs: structural mod ifications result-in g in cnhanced scizure protection relative to motor side cffccts. In: Frontiers in
excitatory amino acid research (CavaSheiro EA, Lehmann J, Turski L, cds), pp227-230. New York: Liss.
Rogawski. MA, Thurkauf A, Yamaguchi S, Rice KC, Jacobson AE, Mattson M V
( 1 989)Anticonvulsant activities of 1-phenylcyclohexylarninc nd its confonna-
tionally restricted anaIog 1,l-pentamethylenetetrahydroisoquinoline. PharmacolExp Ther 249:7(3#-7 12.
Rogawski M A , YamagucM S,Blake PA, Joncs SM , Bieda M,DeCosta BR, ThurkaufA ( 1 992) Anticonvulsant I -phenylcycloalkylaminc analogs: uncompetitiveNMDA antagonists with low motor toxicity. In: Multiple sigma and PCP receptorligands: mechanisms for neuromodutation and neuroproterrion (Kamenka J-M,Domino EF, eds), pp 747-758. Ann Arbor, MI: NPP Hooks.
Rogawski MA, Yamaguchi S, oncs SM, Ricc KC, Thurkauf A, Monn JA (1991)
Anticonvulsant activity of the low affinity uncompetitive N-methyl-D-aspartateantagonist (k)-5-arninocarbonyl-10, l -dihydro-5H-dibenzo[a,a]-cycloheptcn-
5,lO-irnine [ADCI):comparison with the structura l analogs dizocilpine (MK-RO 1)
and carbarnazepine. J Pharmacol Exger Ther 259:3&37.
Rosen JB, Bcrman RF (1985)Pmlonged postictal depression in amygdaln-kindled
rats hy the adenosine anabg , L-phenyliwpropyIadenosinc.Exp Neurol9k549-557.RowleyM, Leeson PD (1992) Excitatory amino acid antagonists. CurrOpin TherPat
2:1201-1221.Rnwley M, Leeson PD, tevenson GI, Moscley AM, Stansfield I, Sanderson I ,
Robinson L, Baker R, Kemp JA, Marshall GR, Foster AC, Crrimwood 5,
Tricklebank MD, Saywell KL (1993) 3-Acetyl-4-hydroxyquinolin-2( H)-ones.Systemically active anticonvulsants acting by antagonism a t theglycine site of theN-methyl-D-aspartate receptor complex. J Med Chcrn 36:33X M 396 .
Rudolphi KA, Schubert P, Parkinson FE, Fredholm RR ( 1 992) Neuroprotective role
of adenosine in cerebral ~schaernia. rends Pharmacol Sci 13:43W5.
Rundfcldt C, Wlaz P, Loscher W (1994) Anticonvutsant activity of antagonists rind
partial agonisrs for the NMDA receptor-associated glycinc site in rhc kindling
model of epilepsy. Brain Res 653:125-1 30.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 75/81
Sacaan Al, Schoepp DD (1992) Activation of hippocampal rnetabotropic excitatory
amino acidmeptors leadsto s e i m ~ s a n deuronal damage.NeurosciLett 1 39:77-82.Sakurada K, Masu Ivl. Nakanishi S ( 1 993)Alteration of Ca2+ emcahilityand sensi-
tivity to M e nd channel blockers by a single amino acid substitution in th e AI-methyl-D-nspartatc receptor. J Riol Chern 26R:41WI 5.
Sanderson G ,Scholfield C N ( 1 986)Effectsofadenosine uptake blockers and sdenos-ine on evoked potentials of guinea-pig o lfactory cortex. Pflbgers Arch 406:2>30.
Sanguinetti MC, Scott AL, Zingaro GJ, Siegl PKS ( 1 988) R R L 3491 5 (cromakalim)
activates ATP-sensitive K' current in cardiac muscle. Proc Natl Acad Sci USA85:8360-8364.
Sanna E, erra M, Cossu A , Colombo G ,FoIlcsa P, Cuccheddu T, ConcasA, BiggioG ( 1 993) Chron ic ethanol intoxication induces differential effccts on GABA, and
NMDA receptor function in the rat brain. Alcohol Clin Exp Rcs IT : l 1.5-1 23.Scatton B, Avcnet P, cnavidcs , Carter C,DuvergerD, ObIin A, Perrault G , Sanger
DJ, SchoernakcrM ( 1994) Neuroprotcctivepolentialofthe polyamine site-dircctcdNMDA receptor antagonists--ifcnprodil and eliprodil. In: Direct and atlosteric
control of glutamate rcccptors(Pa1freyman MG, Reyno Ids IJ, Skolnick P, ds), pp139-1 54. Boca Raton, FL: CRC.
Schmid-Antomarchi H , Amoroso S, FossetM, LazdunskiM I990)KC hannel open-ers activate brain sulfonylu~a-sensitiveK+ channels and block neurosecretion,
Proc Natl Acad Sci USA 87:3489-3492.SchmutzM, Portet Ch, Jcker A,KlebsK, assoutA, Allgeier H, HeckendornR, Fagg
GE, Olpe H-R, van Riezen H ( 1 900)The competitive NMDA receptor antago nistsCGP 37849 andCGP 3955 are potent, orally active anticonvulsants in rodents.Naunyn-Schmiedeberg's Arch Pharmacol342:6 1 4 6 .
Schoepp DD (1994) Pharmacological properties of metabotropic glutamate recep-tors. In: The metabotropic glutamate receptors (Conn PJ, Patel J, eds),pp 3 1-58.Totowa,NJ: Humana.
Schoepp DD, GarnblcA Y, Salhoff CR, ohnson BG, Omstein Pk 1990a) Excitatory
amino acid-induced convulsions in neonatal rats mediated by distinct receptorsubtypes. Eur J Pharmacol 1X2:42 1 4 2 7 .Schoepp DD, Ornstcin PL, Leander JD, odge D, Salhoff CR, Zernan S, Zimmerman
DM ( 1990b) hamacological characterization of LY233053: a structurally novel
tctrazole-substituted competitive N-methyl-D-aspartic acidantagonistwith ashort
duration of action. J Pharmacol Exp Ther 255: 1301-1308.
Schoepp DD, Omstein PL, Sathoff CR, Leander JD 199I)Neuroprotectant effects ofLY2746 14, a structuratly novel systemically active comp etitive NM DA receptorantagonist. J Neural Transm Gen Secr 8.5: 13 -1 43.
Scholficld CN 1 978) A barbiturate induced intensification of the inhibitory potential
in slices of guinea-pig olfactory cortex. J Physiol (Lond) 275359-566.Schwartz JR, rigatG ( 1989) Phenytoin and carbarnazepine: potential- and frequency-
dependent block ofNa currents in m ammalian myelinated nerve fibers. EpiIepsia
30:226-294.
Sedman AJ, Gilmet GP, Saycd AJ, Posvar EL (1990) Initial human safety and toler-ance study o f a GABA uptake inhibitor, CI-966: potential role of GARA as a
mediator in thc ~athoeencsis f schir~nhreniand mania. Drue D ev Res 21 :235+242.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 76/81
SetyeH 1 942) Antagonism between anesthetic steroid hormones and pentamethylenetetrazol (Metrazol). J Lab Clin Med 27:105 1-1 053.
Serra M, Foddi MC, Ghiani CA, Melis MA, Motzo C, Concas A, Sanna E, RiggioF(1992) Pharmacology of y-aminobutyric acid, receptor complex after the in vivo
administration o f the anxiosclcctivc and anticonvulsant P-cnrboline derivativeabccarnil. J Pham aco l Exp Thcr 263:136%1368.
Serra M, Ghiani CA, Motzo C, PorcedduMS, iggio G 1 994) Long-term treatmentwith abccarnil fails to induce toierance in micc. Eur J Pharmacol259:14.
Seymour PA , Mena EE (1989) In vivo NMD A antagonist activity of th e polyaminespider venom component, argiotoxin-636. Soc Neurosci Abstr 15:1168.
SheardownMJ,Nielscn E0, ansen AJ, Jacobsen P,HonoreT (1 990)2,S-Dihydmxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaEine: neuroprotectant forcercbral ischemia.Science 247571-574.
Simmonds M A (1991) Modulation of th e GABA, receptor by steroids. SeminNeurosci 3:23 1-239.
Simon RL, Lin SS ( 1 993) Potassium channel openers block seizureactivity in anin-vitro model of ep i lqsy . Biophys 164(2 Pr 2):AlOO.
Singh L, Donald AE, Foster AC, Hutson PH, lversen LL, Iversen SD,Kemp JA,
Leeson PD, Marshall GR, Oles RJ, Priestley T, Thorn L, Tricklebank MD, VassCA, Williams RJ ( 1990) Enantiomasof HA-966 3-amino-1hydroxypyrmlid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selectiveglycine/N-methyl-D-aspartate eceptor antagonist, but (-)-HA-966 is a potenty-butyrolactonc-like sedative . Proc Natl Acad Sci USA 87347-35 1.
Singh L,Oles W , Vass CA, WoodruffGN (1991) A slow intravenous infusion of hl-rnethyI-DL-aspartate a s a seizuremodel in themouse. Neurosci Methods 37:227-232.
Skolnick P,Marvizon JC, Jackson RW, Monn JA, RiceKC, Lewin AH (1 989)Block-ade of N-methyl-D-aspartate induced convulsions by I-aminocyclopropane-carboxylates.Life Sci 45;1647-1655.
Skolnick P, Z h w L-M, handler P,Nashed NT, Pennington M, Maccecchini M-L( 1 994)Conantokin-G and its analogs: novel probesof the NMDA receptor assa-ciated polyamine site. In: Direct and allosteric control of glutamate receptors(Palfreyman MG, Reynolds IJ, Skolnick P, eds), pp 15S165. Boca Raton, FL: CRC.
Smith SE, al-Zubaidy ZA, Chapman AG, Meldmm RS 1993) Excitatory amino acidantagonists, lamotrigine and BW 1003C87 as anticonvulsants in the geneticallyepilepsy-prone rat. Epilepsy Res 15:101-1 1 1.
Smith SE, Chapman AG (1993) Acute and chronic anticonwlsant effects of Q(-)CPPcne in genetically epilepsy-prone rats. Epilepsy Res 15:193-1 99.
Smith SE, DiirmullerN,Meldrum RS (1941) The non-N-methyl-D-aspartatereceptorantagonists, GYKI 52466 and NRQX are anticonvuIsant in two animal models ofreflex epilepsy. Eur J Pharmacol 201: 79-1 83 .
Smith SE,Meldturn BS (1992)The glycine-site NMDA receptor antagonist R-(+)-
cis-b-methyl-3-amino-1 -hydroxypyrrolidin-2-one, -687,414 isanticonvulsant n
baboons. Eur J Pharrnacol2 1 I :109-1 I I .
Smith SE, Pawez NS, Chapman AG, Meldrum BS (1995) The y-aminobutyric acid
uptakc inhibitor, tiagabine, is anticonvulsant in two animal models of reflex epi-Icpsy. Eur J Pbarmacol 273259-265.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 77/81
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 78/81
SveinbjarnsdottirS, ander JW, Upton D, Thompson PJ, atsalos PN , HirtD, Emre
M, Lowe D, Duncan JS (1993) The excitatory amino acid antagonist D-CPP-enc(SDZ AA-494) n patients with epilepsy. Epilepsy Res 16:165-1 74.
Swinyard EA, Sofia RD, upferbergHJ ( 1 986) Comparative anticonvulsant activity
and neurotoxicity of felbamatc and four prototype antiepilcptic drugs in mice andrats. Epilepsia 27:27-34.
Swinyard EA, White HS, Wolf HH,Bondinelli WE (1991) Anticonvulsantprofilesofth e potent and orally active GABA uptake inhibitors SK&F 89976-A and SKfeF
100330-A and four prototype anticpilcptic drugs in mice and rats. Epilcpsja32:569-577.
SybirskaE, SeibylJP,BremnerJD, Baldwin RM,Al-TikritiMS, BradbemyC,MalisonRT, Zca-Pance Y, Zoghbi S, During M, Goddard AW , Woods SW , Hoffer PH,Charney DS, Innis RB (1993) ['2'I]lomazenil SPECT imaging demonstrntcs sig-
nificant benzodiazepine receptor reserve in human and nonhuman primatc brain.Neurophamacology 32: 67 1-680.
Tarnawa I, Berzsenyi P, Andrtisi F, Botka P, Hhrnari T, Ling I , K6r(lsi J (1993)
Structure-activity re lationsh ips oE2,3-benzodiazepine compounds with glutamateantagonistic adio n. Bioorg Med Chem Lett 3:Y%104.
Tarnawa I, Engberg. I, Flatman JA ( 1990)G Y M 52466,an inhibitor ofspinal reflexes
is a potent quisqualateantagonist. In: Amino acids. Chemistry, biology and medi-
cine (Lubec ti, Rosenthal GA, eds), pp 538-546. Leiden, The Netherlands:ESCOM.
Taverna FA, Cameron BR, HarnpsonDL, Wang LY,MacDonald JF 1 994) Sensitiv-ity o f AMPA receptors to pentobarbital. Eur J Phannacol267:R3-R5.
TaylorCP 1993)Mechanismof ction of new anti-epileptic drugs. In: New trends n
epilepsy management: therole of
gabapentin (Chadwick D. ed), pp 13-40. Lon-don: Royal Society Medicine Services.Taylor CP (1 994) Emergingperspectiveson the mechanism of action of gabapcntin.
Neurology 44(Suppl 5):s I&S 16.Taylor CP. Vartanian MG, Schwatz RD, Rock RM, CallahanMJ,DavisMD 1990)
Pharmacology of (3-966: a potent G A R A uptake inhibitor, in-vitro and in
experimental animals. h g ev Res 21: 171-1 X5 .
Thomsen C, Klitgaard H, Sheardown M, Jackson HC, Eskesen K, acobsen P,
Tseppendahl S, Suzdak PD 1 994) (n-CCarboxy-3-hydroxyphenylglycine,nantagonist of metabotropic glutamate receptor (mG1uR)la and an agonist of
rnGiuR.2, protects against audiogenic seizures i n DBA/2 mice. 4 N e u r o c h m62:2492-2495.
ThornsenC,Suzdak, D 1993)4Carboxy-3-hydroxyphenylgIycine,n antagonist attype I mctabfltropic glutamatc receptors. Eur J Pharmacol Mol Pharmacol245999-30 1.
ThomsonAM (1988) nhibitory postsynaptic potentials evoked in thalamic neurons
by stimulation of the reticularis nuclcus evoke slow spikes in isolated rat brain
s l i c e d . Neuroscience 25:491-502.Thompson SM, GahwilerBH 1992) Effects ofthe GABA uptake inhibitor iagabine
on inhibitory synaptic potentials in sat hippocampal slicc cultures. J Ncurophysiol
67:1698-1701.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 79/81
Thompson SM,Haas HL. Gahwi l a BH t 992) Comparison of the actions of adcnos-
Inc at pre- and postsynaptic receptors in the rat hippocampus in witro , J Physiol(Lond)451 3347-363.
ThurkaufA,DeCosta B, Y arnagch i S,MattsonM, acobsonAE, Rice KC, Rogawski
M A (1990) Synthesis and anticonvulsant activities of I -phenylcyclohexylarnineanalogs. I Med Chern 33:1452-14%.
TizzannJP,GrifFcy KI, Johnson JA, Fix AS, Hclton DR, choeppDl3 (1994) Intrac-erebral 1S,3R- 1-aminocyciopenmne-l,3-dicarboxylic cid ( 1SJR-ACPD) pro-duces limbic seizures that arc not blackcd by ionotropic glutamate receptorantagonists. Neurosci Lett 162:12-16.
Tran M , Lutfy R, Kwon I, Cni SX, Kcana JFW,Weber E (1994) The anti-convulsant and
antinociccptivceffcct of 5-nitm-6-mcthyl-7-chlorn-2,3quinoxalindioneNMCQX)and 5-nim-6,7-dimethyl-2,3-quinoxalincdioneNDMQX),wo novclNMDAmccp-
torlglycine siteantagonists n thc MESand iomalin tests.SacNcurosciAbstr20: 1240.TrchcrncJM, Ashford MLJ (1.99 ) Thc rcgional distributionofsulphonylusca bindingsitcs in rat brain. Neuroscience 40:523-531.
Tricklebank MD, onorkT, Ivcrsen SP,KempJA , Knight AR,Marshall GR,RupniakNMJ, Sing11 L, Tyc S , Watjen F, Wong EHF 1990)The phanacological proper-ties of the imidazobcnzodiazepinc, FG 8205, a novel paflial agonist a t the benzo-
diazcpinc reccptor. Br I Pharmacol 101 :753-76 1 .Turski L, StephensDN, JensenLIi, Petersen EN, Meldrum BS, atelS,Bondo Hansen
J , Lllschcr W, Schncidcr HH, Schmiechen R (1990 ) Anticonvulsant action ofthe P-carboline abccarnil: studies in rodents and baboon, Papiopapio. J Phamacol
Exp Thcr 253:344-352.Twyman RE, Macdonald RL (1992) Neurosteroid regulation of GABA, receptor
single-channel kinetic propertiesofrnousespinalcord neurons in culture. J Physiol(Land) 456:215-245.
Vartanian MG, Taylor CP (199 1) Different stereoselectivity of the enantiomers of
HA-966 (3-amino- l -hydroxy-2-pysrolidinonc)or nevroprotective and anti-convulsant actions in viva. Neumsci Lett 133:109-1 12.
Vaught JL,Wa uquierA (1991) Evidence for a unique nteraction of loreclezolewiththe G A B A receptor complex. Umg Dev Res 23: 18 1-1 89.
Verdoorn TA. Burnashev N,Monyer H , Secburg PH, Sakmann B (1991) Structuraldeterminants o f ion flow through recombinant glutamate reccptor channels. Sci-ence 252: 1715-1 T 18.
Verdoorn TA , Johansen TH, rcjw J, Nielsen E 0 1994)Selective block a f recom-binant glur6 receptors by NS-102. a novel nan-NMDA receptor antagonist. Eur JPharmacol269:43-49.
von Krosipk M, al T, McCormick DA ( 1 993) Cellular mechanisms of a synchro-
nized oscillation in the thalamus. Science 261:36I-364.
WaffordKA, Bain CJ, Quirk K,McKernanRM, Wingrove PB, Whiting PJ,Kernp JA
(1994)A novel allosteric modulatory site on the GABA, receptor p-subunit.Neu-ron 123775-782.
Wafford KA. RainCJ, hiting PJ,Kemp JA (1993)FunctionaI comparison of the roleof y subunits i n recornbjnont human y-arninobutyric n~id~lhcnzodiazepinecccp-tors, Mol Pharmacol 44:4 37 442 .
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 80/81
Wahl F, Allix M, Plotkine M, Boulu RG (1993) Effect o f siluzole on focal cerebralischemia in rats. Eus Pharrnacol230:209-214.
Wang X-J, Rinzel J, RogawskiM (1991) A model of the T-type calcium current and
th e low-threshold spike in thalamic neurons. J Neurophysief 66:839-R50.
Watjen F, Nielscn EC9, Drejer J, Jensen LH (1993) Isatin oxamines--A novel seriesof bioavailablc non-NMDA antagonists, Bioorg Med Chem Lett 3: 105,106.
Watkins JC (199 1 ) Somc chemical highlights in the dcveloprnent of excitatory aminoacid pharmacology. Can J PhysioI Phamacol 69:1064-1 075.
Watson GB, Lanthorn TH (1990) Pharmacological characteristics of cyclic homo-logues of glycine at the N-mcthyl-D-aspartate receptor-associated glycine site.
Ncuropharmacology293727-730.Wauquier A, Fransen J, Melis W, shton D, illardin I-M, Lewi PJ, Van Clemen G,
Vaught J , Janssen PAJ ( 1 990) Loreclczol~ R 72 063): an anticonvulsant chemi-
cally unrelated to prototype antiepileptic drugs.Drug Dev Res t 9375-392.
Weston AH, Edwards G ( 1992) Recent progress in potassium channel: opener phar-macology. Biochem Pharmacol43:47-54.
Whitcomb K,Lupica CR, Roscn JB , B e m n RE (1990) Adenosine involvement inpostictal events in amygdala-kindlcd rats. Epilepsy Rcs 6: 171-1 79.
Whitc G ( 1994)The broad spectrum anticonvulsant ADCI 'blocks TTX sensitivevoltage-activated Na channel currents in NE1-115 mouse neuroblastoma cells.Soc Neurosci Abst 20: 239.
Whitten JP, Baron BM, Muench D, Miller F,White HS, McDonald IA (1990) (R)-4-
0x0-5-phosphononorvaline: new competitiveglutamateantagonist at thc NMDA
receptor complex. J Med Chern 33:2961-2963.
Wiesner JB, Zimring 5 1994) Inhibition ofmaximai electroshock (MES) seizures byA1 adenosine receptor agonists. Soc Neurosci Absrr 20: 1641.
Willetts J, Balster RL, Leander J D (1990) The behavioral pharmacology ofNMDAreceptor antagonists. Trends Neurosci 1 1 :423-428.
Williams K (1993) Ifenprodil discriminates subtypes of the N-methyl-D-aspartatereceptor: selectivity and mechanisms a t recombinant heterom eric receptors. Mol
Pharmacol44:R5 1 4 5 9 .
Williams K, Dawson VL, omano C, Djchter MA, MolinoffPB (1990)Characteriza-
tion of potgamines having agonist, antagonist, and inverse agonist effects at th e
polyamiae recognition site of th e NMDA receptor. Neuron 5 : 19%20R.Williams K. Romano C ,Dichter MA, MolinoffPB (1 991) Modulation of theNMDA
receptor by polyarnincs. Life Sci48:46!W9X.
Williams K, Zappia AM, Ptitchett DB, Shen YM, Mofinoff PI3 (1994) Sensitivity o f
the N-methyl-D-aspartate receptor to plyamincs is controlled by NR2 subunits.Mol Pharmacol45:X03-809.
Wingrovc PR , W afford Kb, ain C.Whiting P3 1994) The modulatory action of
~orcclezolet the y-aminobutyric acid type A receptor i s determined by a single
amino acid in the p, and p, subunit. Proc Natl Acad Sci USA 91:456W533.
Witkin JM, Tortella FC (199 1 ) Modulators o fN-methyt-D-aspartate protect against
diazepam- or phenobatbita&resistant cocaine convulsions.Lifc Sci 4X:PL5 1-PL56.
Wood PR , Browne GP, Pugh S (I 88) Propofol infusion for the treatment of status
epilcpticus. Lancct 1 :480.
8/8/2019 Rogawski Epilepsy Neurotherapeutics1996compress
http://slidepdf.com/reader/full/rogawski-epilepsy-neurotherapeutics1996compress 81/81
Epilepsy
Woodward RM, Hucttner JE, Guastella J, Weber E (1 993) In virm p h a m a c ~ l ~ g i c a l
chamctcrization of ACEA-102 1:a potent NM DA receptor glycine siteantagonist.
Soc Neurosci Abstr 195'1 8.
Yarnaguchi S, DoncvanSD, Rogawski MA(1993)AntEconvulsantactivity ofAMPA1kainate antagonists: comparison of GYKI 524h(i and NBQX in maximal clec-troshock and chcmoconvulsant m odels. Epilepsy Res 15:179-1 84.
Yoon KW, Rothman SM 1 991) Adenosine inhibits excitatory but not inhibitorysynaptic transmission in the hippocampus. J Neurosci 1 1:1375-1 380.
Yucn AW (1994) Lamotrigine: a scview of antiepileptic efficacy. Epilepsia
3S(SuppF 5 ) : 5 3 3 4 3 6 .
Zettcrstrom T, Vcrnet L, Ungersttdt U, TossmanU, onzen B, Frcdholm BE 1 982)Purine lcvcls in the intact rat brain. Studies with an implanted perfused hollowfibre. Neurosci Lett 29:1 11-1 15.
Zhang G, Franklin PH,Murray TF (1993) Manipulation o f endogenousadenosine inth e rat prepiriform cortex modulates seizure susceptibility. J Phannacol Exp Ther264:1415-1424.
Zhang G , Franklin PM,M u m y TF (1994a) Activation of adenosine A1 receptorsunderlies anticonvulsant effect of CGS21680. Eur J PharmacoI 255:239-243.
Zhang L, Zheng X, Paupard M-C, Wang AP, Santchi L, Friedman LK, Zukin RS,Bennett M V L '1994b) perminepotentiation of recombinant N-methly-D-aspar-
tare receptors is affected by subunit composition. Proc Natl Acad Sci USA
9 :10,883-1 0.887.
Zhao T-3,Chiu TH , Rosenberg HC (1994) Reducedexpression ofy-aminobutyric acid
type Albenzadiazepine receptor y2 and a5 subunit rnRNAs in brain regions of
flurazepam-treated rats. Mol Pharrnacol45:6574h3.
Zhu Y , rn W R 1992)Block of sodium channel current by anticonvulsant U-54494Ain mouse neuroblastorna cells. J Phamacol Exp Ther 260: 1 1tL116.
Zhu Y, I r n WR, Lewis RA , Althaus JS, Cazers AR, Nielsen JW , Palmer JR, Von
Vaigtlander PF ( 1 993) Two metabolites o f anticonvulsant W-54494A: their
anticonvulsant activity and interaction with sodium channel. Bmin Res 606:5&55.Zhu Y, Irn WR, Lewis RA, Von Voigtlander PF ( 1 992) Comparison of pyrrolidinyl
and piperidinyl benzamidcs for their anticonvulsant activity and inhibitory action