Richard A. Glennon et al- Methcathinone: A New and Potent Amphetamine-Like Agent

8/3/2019 Richard A. Glennon et al- Methcathinone: A New and Potent Amphetamine-Like Agent

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Pharmacology Btochem~stry &Behawor,Vol 26, pp 547-551 CopyrightPergamonJournals Ltd , 1987 Pnntedm the U S A 0091-3057/87 3 DO+ DO

M e th c a th in o n e : A N e w a n d P o t e n tA m p h e t a m i n e - L i k e A g e n t

R I C H A R D A . G L E N N O N , * M A M O U N Y O U S I F , *N O R E E N N A I M A N * A N D P E T E R K A L I X ' t

*Department o f Medtctnal Chemtstry, School o f Pharmacy, Medical College of VtrgintaVtrglma Commonwealth Umversity, Rtchmond, VA 23298"tDepartment of Pharmacology, Umverstty Medical Center, UntversttO de Geneve, Geneva, SwttzerlandRece ived 12 September 1986

GLENNON, R A , M YOUSIF, N NAIMAN AND P KALIX Methcathtnone A new andpotent amphetamtne-hkeagent PHARMACOL BIOCHEM BEHAV 26(3) 547-551, 1987 --The purpose of the present investigation was to examinethe effect of N-monomethylat~on of phenyhsopropylam~ne derivatives on amphetam~ne-hke act~wty In test s of st~rnulusgenerahzat~on using rats trmned to discriminate 1 0 mg/kg of (+)-amphetamine from sahne, the N-monomethyl derivativesof i-(X-phenyl)-2-aminopropane, where X=2,4-d~methoxy (2,4-DMA), 3,4-d~methoxy (3,4-DMA), 2,4,5-tnmethoxy(2,4,5,-TMA), and 2-methoxy-4,5-methylened~oxy (MMDA-2), d~d not produce amphetamine-appropriate respondtng atthe doses evaluated However, the N-monomethyl derivative of cath~none 0 e , methcathmone), hke cathmone, resulted mstimulus generahzatlon Further studies w~th thts agent revealed that (a) ~n the amphetamme-tramed ammals,methcathmone (ED50=0 37 mg/kg) ~s more potent than racem~c cath~none or racem~c amphetamine (ED50=0 71 mg/kg ~nboth cases), (b) methcathmone ~s capable of mduc~ng release of radioactivity from [aH]dopam~ne-prelabeled tssue of ratcaudate nucleus ~n a manner s~mdar to tha t observed w~th cathlnone, amphetamine, and methamphetamlne, and (c)methcath~none ts more potent than cath~none as a locomotor stimulant ~n m~ce as determined by their effect on spontaneousactivity The results of the present study prowde evidence for a structural analogy between the prototyplc psychostlmu-lants amphetamme/methamphetam~ne and cathmone/methcath~none, and lend further support to the concept that am-phetamine and cathmone correspond m their pharmacological effectsCathlnone Methc ath~none Drug d~scrtmmat~on Central stimulants MDA AmphetamineMethamphetam~ne Release Spontaneous ac t~wt y MDM A

PHENYLISOPROPYLAMINES (PIAs) can produce avariety of pharmacological effects dependi ng upon the pres-ence and location of pendan t substlt uent groups [5,14]. Theparent compound of this famdy of agents, phenyhso-propylamine itself (i.e , amphetamine), is a psychostlmu-lant, whereas certain methoxy-substltuted derivatives, forexample 1-(2,5-dlmethoxy-4-methylphenyl)-2-ammopropane(DOM), are halluclnogemc in humans [14] Using a drug dis-criminatio n paradigm with rats trained to discr iminate either(+)-amphetamine (AMPH) or DOM from saline, we haveexamined a large series of PIAs m tests of stimulus gener-ahzation m order to determine which agents produceAMPH-hke, and which produce DOM-hke, effects (e.g., [5,9, 16]). In the course of our studies, we have not ed thatN-monomethylatlon of those PIAs that produce DOM-hkeeffects reduces their potency, whereas N-m onomethylatlonof amphetamine (to afford methamphetamine) has little ef-fect on AMPH-hke potency. To confLrrn and extend theseresults, it was of interest to investigate the activity of severaladditional N-monomethyl PIA analogs in amphetamine-trained ratsBecause the stimulant effects of amphetami ne and relatedPIA stim ulants are generally explained by an Induction ofrelease at CNS catecholarmne storage sites [10,12], compari-sons were planned, for any N-methyl derivatives that

produced AMPH-stlmulus generalization, with regard totheir capacity to in duce release at doparnlnergic nerve termi-nalsSuch studies should provide us with a better understand-mg of the effect of N-methylation on amphetamine-like ac-tivity and might have a direct beanng on the action ofstructurally-related drugs of abuse such as MDA and itsN-mon ometh yl derivative MDMA (see below). More Impor-tantly, info rmation wdl be obtain ed with regard to the rela-tionship between molecular structure, amphetamine-ltke ac-tivity, and mechanism of action.METHODRattonale for Drugs Employed

Cathinone was selected for evaluation because It is one ofthe few PIA derivatives that retains poten t amphetarmne-hkecharacter [16], furt hermore, its N-mo nome thyl analog hasnot been previously pharmacologically characterized. Inaddition, we also wanted to exarmne the effect (In am-phetamine-trained animals) of N-monomethylation ofexamples of two other types of agents: (1) PIAs thatproduce DOM-hke effects [i e., l(2,4-dimeth oxyphenyl)-2-ammopropane (2,4-DMA), 1-(2,4,5-tnmethoxyphenyl)-2-ammopropane (2,4,5-TMA), and 1-(2-methoxy-4,5-methyl-

547


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548 GLENNON , YOUSIF, NAIMA N AND KALIX

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/~2 0~5MC C M A A

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Effect of methcathinone (MC), cathinone (C), metham-phetamlne (MA), and amphetamine (A) in rats trained to discrimi-nate 10 mg/kg of (+)-amphetamine from saline All four agents wereracemates, each point reflects the results obtained with fouranimals The Y axis represents the number of responses (as a per-cent of total responses) made on the amphetamine-appropriatelever

enedloxyphenyl)-2-amlnopropane (MMDA-2)] and (2) astructurally-related PIA that produces neither DOM- norAMPH- hke effects 0 e, 3,4 -DMA) [5,9]The purpose of examining 2,4-DMA and 2,4,5-TMA isthat while these agents produce DOM-hk e effects (i.e., resultin DOM-stlmulus generalization), they produce partial gen-erahzat~on in AMPH-trained animals, suggesting that theypossess a stimulant component of action [9]. This IS consis-tent with the results of studies In humans, though hal-luclnogemc, these agents produce considerable centralstimulation [14] MMDA-2, the 2-methoxy analog of 1-(3,4-methylenedloxyphenyl)-2-amlnopropane (3,4-MDA,"MDA"), reportedly produces subjective effects in humanssimilar to those of MDA [14], in humans, MDA producesboth hallucinogenic and central stimulant effects [14] Thus,N-monomethylatlon of these agents m~ght enhance theirAMPH-hke character in the same manner as N-monomethylatlon of MDA, resulting ~n MDMA("Ecstasy"), enhancing ~ts AMPH-hke character [5, 7, 8]3,4-DMA was examined for several reasons although ~tdoes not result ~n AMPH-stlmulus generahzat~on [5] and ~snot a locomotor stimulant in mice [15] ~t appears to producesome amphetamlne-hke effects in rodents [1], it constitutesan "op en ed " m ethylenedloxy bridge analog of MDA, and itresults In stimulus generahzatlon m MDA-trmned animals[8] Here too, N-mon omethylat ion m~ght enhance AM PH-hke characterD r ug D i s c r i m i na t i on S t ud i e s

Six male Sprag ue-Da wley rats (ca 250-300 g) were usedin these studies. The animals were trained (15-m~n trainingsession) to d~scrxminate lntraperltoneal injectmns (15-rainpre-sessxon ln jectmn Interval) of 1 0 mg/kg of ( +)-amphetamine sulfate from vehicle (sterile 0.9% saline) undera variable interval 15-sec schedule of reinforce ment for food(sweetened powdere d milk) reward. Standard two-leve r op-erant chambers (Coulbourn Instruments model E 10-10) wereused The exact training procedure followed that which wehave already described in detail elsewhere [9]. Daily trmmngsessions were conducted with (+)-amphetamine (1 0 mg/kg)

TABLE 1RESULTS OF STIMULUSGENERALIZATIONSTUDIES USINGANIMALS TRAINED TO DISCRIMINATE10 mg/kg OF (+)-AMPHETAMINE FROM SALINE

Agent Dose* N? Responding* Response Rate(+)AMPH 10 6/6 93% (3) 133 (22)Sahne (1 ml/kg) 6/6 10% (5) 13 7 (18)2,4-DMMA 50 4/4 16% (10) 122 (19)80 3/4 8% (8) 47 (15 )100 2/4 27% (3) 56 (2 8)3,4-DMMA 4 0 4/4 1% (I) 155 (4 1)60 3/3 2% (1) 5 1(1 7)

8 0 0 / 4 - -2,4,5-TMMA 20 4/4 0~ 13 2 (3 7)40 4/4 1% (1) 186(1 9)60 3/3 5% (3) 149 (43)100 4/4 8% (6) 49 (0 9)MMDMA 20 4/4 10% (8) 20 9 (6 1)40 3/4 0% 11 0 (55)60 4/4 9% (8) 99 (4 1)7 0 0/4 - -8 0 0 / 4 - -10 0 1/4 - -

*Dose in mg/kg fN=Number of rats responding/number to re-ceive drug SNumber of responses (as a percent of total) made on theamphetamine-appropriate lever , followed by _+SEM Data obtmneddunng 2 5-mIn extinction session Mean responses/mln followed by_+SEM Data obtmned during 25-m~n extinction se ss lo n- -D~sruptlon of behavior (1 e , no responding)

or sahne (1 0 ml/kg), on every fifth day, learning was as-sessed during an initial 2 5-mln non-reinforced (extinction)period foll owed by a 12 5-mln trmnmg session Data col-lected dunng the extmct~on period included responses permm (~ e, response rate) and number o f responses on the(+)-amphetamine-designated lever (expressed as percent oftotal responses)Tests o f stimulus generahzatlon were conducted ~n orderto deter mine ~f the N-m ethyl analogs wo uld substitute for the(+)-amphetamine-stimulus, racemlc amphetamine, metham-phetamme, and cathinone were Included for purposes ofcomparison. Dunng this phase of the study, maintenance ofthe (+)-amphetamlne/sahne discrimination was insured bycontinuation of the training sessions. On one of the two daysbefore a generalization test, half the ammals would receive(+)-am phetamine and the other half would receive saline.after a 2 5-min extinction session, training was continued for12 5 mln Anim als not d~scrlmlna tlng drug from saline 0 e ,animals not making >80% of their responses on theamphetamine-designated lever after adm~mstration of 1 0mg/kg of (+)-amphetamine, or making >20% of their re-sponses on th~s same l ever after administration of saline)were excluded from the subsequent generahzat~on test ses-sion Dunn g the ~nvestlgations of stimulus generahza tlon,test sessions were interposed amongst the training sessionsThe anim als wer e allowed 2 5 rain to respond under non-reinforcement conditions, the ammals were then removedfrom the operant chambers and returned to their individualhome cages An odd number of tralmng sessions (usuallyfive, but never less than three) separated any two gener-ahzatlon test sessions Doses of the challenge drugs were


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METHCATHINONE 549O O

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FIG 2 Effect of racemlc methcathlnone as compared to S(-)-cathlnone (upper panel), and of S(+)-methamphetam~ne as com-pared to S(+)-amphetamlne (lower panel), on the release of radioac-tivity from rat caudate nucleus prelabeled w~th [aH]dopamlne T~s-sue samples were exposed dunng 15 mln to a g~venconcentration ofthe N-methyl compounds and then, after an interval of 24 m~n, o thesame concentration of the corresponding des-methyl compoundEach fraction corresponds to 3 m~n of effiux

administered in a random sequence using a 15-mln pre-session injection ~nterval to, routinely, groups of three orfour rats Stimulus generalization was said to have occurredwhen the animals, after given a dose of challenge drug, made80% or greater of their responses on the (+)-amphetamine-appropriate lever. Ammals making fewer than 5 total re-sponses during the entire 2.5-m~n extinction session wereconsidered as being disrupted Where generalization oc-curred, ED50 values were calculated from the dose-res ponsedata by method of Fin ney [3] The ED50 values are doses atwhich the animals would be expected to make 50% of theirresponse s on the drug-designated lever All solutions wereprepared fresh dady ~n sterile 0 9% sahne and all mject~onswere made via the ~ntrapentoneal route A 15-mm pre-session inject ion ~nterval was used throughoutLocomotor Acttvtty Studies

Male (ICR) mice were acchm ated in individual photocellact~wty chambers for 20 mm and were then removed for anlntraperlton eal injection of either saline or drug Each mo usewas retur ned to a chambe r and, 20 mln later, interr uptions ofthe photocell beam were recorded for a period of 10 mln Theapparatus and the procedure have been previously reportedm detail [13]

Release ExperimentsSamples of rat strlatal t~ssue, d~ssected from the head ofthe caudate nucleus, were cut with a scalpel into cubesmeasuring less than 1 mm m each dimension. The tissue was~ncubated for 20 m~n at 37 degrees C ~n 1 ml of a solutioncon tain ing (mmol/1) NaCI 136, KCI 5 6, NaHCO3 20.0,

NaHzPO4 1.2, CaC12 2.2, MgCI~ 1 2, glucose 5.5, and towhich 12/~CI [aH]dopamme (0.8 nmol dopam~ne) had beenadded. Du ring the incub ation (as well as during the subse-quent superfus~on), the mediu m was conti nuou sly oxygen-ated w~th a mixtur e of 95% oxygen-5% carbon dioxide (pH7.3) At the end of the labeh ng period the txssue samp leswere transferred to a perspex perfuslon chamber of approx-imately 0 3 ml volume. They were then superfused at a rateof 0.5 ml/m~n with the abov e sol utio n at 37 degrees C. Th esponta neous efflux of radioactivity from the txssue stabd~zeddur ing an ~nit~alwashing period of one hour to a steady back-ground which was not altered by the flow stop which wasnecessary for switching to a modified superfuslon medium.The test sub stan ces were dis solve d ~n d~stdled water a fewm~nutes prior to use and they were added at a 400-fold con-centratton at least to the superfus~on medium. Dunng theexperimental period, the superfusate was collected m suc-cessive 3-mln fractions and its tritium content was deter-mined by scintillation counting. The figures show typical ex-periments with results representative of several analogousobservations

Drugs(+)-Amphetamine was used as ~ts sulfate salt, all otheragents were used as their hydrochlonde (HC1) salts. S(-)-cathinone HC1 and racem~c cathlnon e HCI were obtained asgifts from the Umted Nations Narcotics Laboratory.Racemic amphetamine HC1, racemic methamphetammeHCI, racem~c N-monomethyl-l-(3,4-d~methoxyphenyl)-2-anu-

nopropane HCI (3,4-DMMA), and (+)-methamphetam~nehad been previously synthesized m our laboratory and wereavailable from an earher study. With the exception ofmethcatlunone, all of the new N-methyl derivatives wereprepared by acylation of the corresponding primary aminewith ethyl chloroformate, followed by reduction of the result-ant carbamate esters w~th hthium alummum hydride,ethere al solu tions of the free bases wer e treat ed w~th HCI gasto precipitate the HC1 salts which were sub sequen tly recrys-talhzed from absolute ethanol (layering with anhydrousether when necessary) Infrared and proton nuclear magneticresonance spectra are consistent w~th the assigned struc-tures Melting points (degrees C) and results of micro-analysis are as follows (calculated/found): N-monomethyl-l-(2,4-d imethoxyphenyl)-2 -am~nopropane HCI (2,4-DMM A) (mp=128--130), C1~HI~NO2"HCI'I/4H~O (C 57 59/57 46%, H 8.25/8.15%, N" 5.60/5 91%); N-mo nome thyl -1-(2-methoxy-4,5-methylenedIoxyphenyl)-2-amInopropaneHC1(MMDMA) (mp =166- 167 ), CI~H~TNO~'HCI (C 55.49/55 55%, H 6.99/7.02%, N" 5 39/5.36%); N-mon ome thy l-1-(2,4,5- tnmethoxyph enyl)-2-amln opropane HCI (2,4,5-TMMA) (mp =15 1-1 53) , C~3Hz1NO3"HC1 (C 56 62/5669% , H 8.04/8.07%, N 5.08/5.05%) Racem~c N-monomethylcathlnon e HCI ("methcathlno ne"), meltingpoint 185-187 degrees C (lit mp 183 [4]), was p repar ed b y thechromic acid oxidation of (-)-norephednne in a mannersimilar to that of a pubhsh ed procedure [2] Even thoughoptically active starting material was used, racem~zatlon ap-


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550 GLENNO N, YOUSIF, NAIMAN AND KALIXE 250

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D o s e ( m g / k gFIG 3 Effect of methcath~none (MC) and racem~c cath~none (C) onspontaneous locomotor activity S=sahne control (n=54) Eachdose of drug was evaluated ~n 12 m~ce (except that n=6 for the 10mg/kg dose of cath~none), results are expressed as means_+SEM

pears to have occu rred du nng ox idation ~n that the produ ct ~soptically inactive as determined by polanm~try

RESULTSDrug Dtscrtmtnatton Studtes

Tests of stim ulus generallzaUon w~th the ch allenge drugswere conducted once the ammals had been trained to dls-criminate (+)-amphetamine from sahne. The (+)-amphetami ne-stimu lus generahzed to racemlc amphetamine[ED50=071 (0.43-1.15) mg/kg], cath~none (ED50=071(0.46-1.03) mg/kg], methamph etamlne [ED50=0.49 (0 31-0.78) mg/kg], and methcath~none [ED50=0.37 (0.22-0.61)mg/kg] (F~g. 1) The (+) -am phe tami ne stimulus did not gen-erahze to 2,4-DMMA, 2,4,5-TMMA, nor to MMDMA (Table1) At 10 mg/kg, Le., at more than twent y times the ED50dose of racemlc methamphetam~ne, 2,4-DMMA and 2,4,5-TMMA produced less than 30% amphetamine-appropriateresponding, because the ammals' response rates were al-ready depressed by more than 50% at the h~ghest dosestested, h~gher doses of these agents were not evaluated.3,4-DMMA and MMDMA produced sahne-hke effects at 6mg/kg and, at h~gher doses, p roduced disruption of behavior(Table 1)Release Experiments

Because methcath~none was the only new N-methyl de-rivative that produced (+)-amphetamine-appropriate re-sponding, it was the only derivative examined w~th respectto a releasing effect on dopam~nerglc nerve terminals, ~nthese experiments, the effects of racem~c methcathlnonewere compared with those of S(-)-cath~none, S(+)-amphetamme, and S(+)-methamphetamlne When shces ofrat caudate nucleus that had been prelabeled w~th[3H]dopam~ne were superf used with a s oluUon cont mmn glow concent ration s of methcath~none, a rap~d and reversible~ncrease of the release of radioactlwty occurred. The reac-tion was dose-depend ent Subseq uent superfusion of thepreparation with S(-)-cath~none at the same concentrationcaused an ~ncrease of efflux that was of similar amphtude.the two agents were also found to be equlpotent when theywere tested at a some what h~gher conce ntr atio n (F~g 2,upper panel) Analogous observat ions were made when

S(+)-amphetamlne and S(+ )-methamphetamlne were com-pared under the same experimental conditions (Fig 2, lowerpanel) Slmdar results were obtained when the agents weretested ~n inverse orderLocomotor Acttvtty Studtes

The effects of methcath~none and racem~c cath~none onspo ntan eous activ ity ~n m~ce are sho wn in Fig. 3. At dose s of3 to 10 mg/kg, the effect of cathlnone was s~mdar to thatproduced by sahne (1 e, baseline responding) At compara-ble doses, methcathlnone produced a dose-related increaseIn locomotor activity (Fig 3)DISCUSSION

N-Monomethylat~on of the hallucinogenic PIAs 2,4-DMA, 2,4,5-TMA, and MMDA-2 (to afford 2,4-DMMA,2,4,5-TMMA, and MMDMA, respectively) did not result inamphetam~ne-hke agents (~ e, the amphetam ine-sti mulus didnot generahze to any of the three agents at the doses eval-uated) (Table 1) Becau se 2,4-DMA and 2,4,5- TMA are fairlypot ent h allucin ogenic agents to b egin with [14], it ~s hkelythat their N-monomethyl derivatives m~ght stdl possesssome residual hallucinogenic activity, and this might accountfor the decrease ~n response rates and/or the dtsruptlon ofbehawor noted at the higher doses. Likewise, theamphetamin e-stimul us did not generalize to 3,4-DMMA, theN-mono methyl derivative of 3,4-DMA We had earherdemonstrated amphetamin e-stimulu s generalization to MDAand ~ts monomethyl derivative MDMA, due to the closestructural resemblance of 3,4-DMA and 3,4-DMMA withMDA and MDMA, we mus t conclude that there is somethingumque about the methylenedl oxy bridge regarding ~ts contri-bution to amphetamme-hke stimulus effects. Nevertheless,the presence of the methylenedloxy group does not assureamphetamine-like properties in that MMDMA producessaline appropriate responding even at nearly l0 t~mes theED50 dose of racemlc amphetamineAs is the case with amphetamine, however, N-mon-omethylatlon of cathlnone does result in an activeagent (l.e, methcathlnon e) both with respect to ampheta-mme-h ke stimulus effects (F~g l) and release from dopaml neterminals (Fig 2) Because neither of these experimentsprovide direct information as to central sum ulant properties,methcathmone and cathmone were examined with regard totheir effect on locomotor activity of mice Racemlccathlnone has previously been shown to be a fairly potentloco moto r stimul ant [6, II , 15], ~n the pre sent stud y,methcathlnone was found to be several umes more potentthan cat hmon e ~tself (Fig 3)The present observations are of interest for several rea-sons (1) N-monomet hylatl on enhance d (or at least did notdecrease) the behavioral potency only of an agent withdemonstr ated amphet amme-hke effects (! e , cathmone), (2)unhke methcathlnone, other derivatives of cath~none are,w~th regard both to behavioral activity and release fromdopamine terminals, far less potent than the parent com-pound [12], (3) the present findings prowde a structuralanalogy between the prototyplc psychost~mulants am-phetam~ne/methamphetamme and cathmone/methcathmoneThus, the cathlnone molecule shares not only the phar-macological profile of amphetamine I11], but also shares thefeatures that the S-~somer ~s more potent than theR-enant iomer [5, 6, 10, 16] and that N-mono methyla tlon af-fects activity in a simdar manner


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M E T H C A T H I N O N E 55 1

ACKNOWLEDGEMENT STh ~ s w o r k w a s s u p p o r t e d , m p a r t , b y U S P u b h c H e a l t h S e r w c eg r a n t D A - 0 1 6 42 a n d b y f u n d s f r o m t h e W o r l d H e a l t h O r g a m z a t~ o nW e w o u l d a l s o h k e t o e x p r e s s o u r a p p r e c i a t i o n t o B e t s y M a c k f o rh e r a s s i s t a n c e ~ n t h e d r u g d i s c r i m i n a t i o n s tu d t e s , a n d t o D r B i l lyM a r t i n f o r c o n d u c t i n g t h e l o c o m o t o r s t u d i e s

R E F E R E N C E S

1 B a r f k n e c h t , C F a n d D E N ~ c h o ls E f f ec t s o f S ( + ) - a n dR ( - ) - 3 , 4 - d t m e t h o x y p h e n y h s o p r o p y l a m ~ n e s ~ n t h e r a t J M e dC h e m 15: 109-110, 19722 B n t t s h P a t e n t 76 8 , 7 72 , F e b r u a r y 2 0 , 1 95 7 ( C h e m A b s t r 51 :15552 , 1957 )3 F ~ n n e y , D P r o b t t A n a l y s ~ s L o n d o n C a m b r i d g e U n i v e r s i t yP re s s , 19524 G e r m a n P a t e n t 6 34 , 0 0 2 , A u g u s t 1 4 , 1 93 6 ( C h e m A b s t r 31: 1821,1937 )5 G l e n n o n , R A D ~ s c n m m a U v e s tt m u l u s p r o p e rU e s o fp h e n y h s o p r o p y l a m i n e d e n v a U v e s D r u g A l c o h o l D e p e n d 17 :119-134, 19866 G l e n n o n , R A a n d D S h o w a l t e r T h e e f fe c t o f c a t h ~ n o n e a n d

s e v e ra l r e l a t e d d e r i v a t i v e s o n l o c o m o t o r a c t i v it y R e s C o m m u nS u b s t A b u s e 2: 186--192, 19817 G l e n n o n , R A a n d R Y o u n g M D A A p s y c h o a c t i v e a g e n tw ~ t h d u a l s t t m u l u s e f f e c t s L t f e S c t 34 : 37%3 83 , 19848 G l e n n o n , R A a n d R Y o u n g M D A A n a g e n t t h a t p r o d u c e ss t im u l u s e f f e c t s s~ m l la r t o t h o s e o f 3 , 4 - D M A , L S D a n d c o c a i n eE u r J P h a r m a c o l 9 9 : 2 4 % 2 5 0 , 1 9 849 G l e n n o n , R A , R Y o u n g a n d A E H a u c k S t r u c tu r e - a c t~ v t t ys t u d i e s o n m e t h o x y - s u b s t l t u t e d p h e n y h s o p r o p y l a m t n e s u s i n gd r u g d ~ s c rl m tn a t ~ o n m e t h o d o l o g y P h a r m a ~ o l B t o c h e m B e h a v22 : 723-729 , 1985

1 0. K a h x , P T h e r e l e a s i n g e f f e ct o f t h e ~ s o m e r s o f t h e a l k a l o t dc a t h t n o n e a t c e n t r a l a n d p e r i p h e r a l c a t e c h o l a m m e s t o r a g e s ~ te sN e u r o p h a r m a c o l o g y 2 5 : 4 9 % 5 0 1 , 1 9 86I 1 K a h x , P a n d O B r a e n d e n P h a r m a c o l o g i c a l a s p e c t s o f t h ec h e w i n g o f k h a t l e a v e s P h a r m a c o l R e v 37 : 14%164 , 19851 2 K a h x , P a n d R A G l e n n o n F u r t h e r ev i d e n c e f o r a na m p h e t a m ~ n e - h k e m e c h a m s m o f a c U o n o f t h e a l k a l o i dc a t h m o n e B t o c h e m P h a r m a c o l 35 : 3015 -3019 , 19861 3 R e y n o l d s , M L , P J L ~ t tl e , B F T h o m a s , R B B a g l e y a n dB R M a r U n R e l a t i o n s h i p b e t w e e n t h e b ~ o d ~ sp o s~ t ~ o n o f[ a H ] s o m a n a n d i t s p h a r m a c o l o g i c a l e f f ec t s T o x t c o l A p p l P h a r -m a c o l 8 0 : 4 0 % 4 2 0 , 1 9 8 51 4 S h u l g i n , A T P s y c h o t o m ~ m e t ~ c d r u g s S t r u c t u r e - a c t i v i t y r e l a -t i o n s h i p s I n H a n d b o o k o f P s y c h o p h a rm a c o l o g y , vo l 11 , e d i t e db y L L I v e r s e n , S D I v e r s e n a n d S H S n y d e r N e w Y o r kP le nu m P re s s , 1978 , p 24315 V a n d e r S c h o o t , J B , E J A n en s , J A v a n R o s s u m a n d J AT M H u r k m a n s P h e n y h s o p r o p y l a m m e d e r i v a t i v es , s t r u c t u r ea n d a c t i o n A r z n e t m t t t e l f o r s c h 12 : 902-907 , 19621 6 Y o u n g , R a n d R A G l e n n o n D ~ s c n m m a t~ v e s t i m u l u s p r o p e r -t~ e s o f a m p h e t a m i n e a n d s t r u c t u r a l l y r el a t e d p h e n a l k y l a m m e sM e d R e s R e v 6 : 99 -130 , 1986

Richard A. Glennon et al- Methcathinone: A New and Potent Amphetamine-Like Agent

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Transcript of Richard A. Glennon et al- Methcathinone: A New and Potent Amphetamine-Like Agent