Post on 02-Jun-2018
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1$% Acetchoi!e#tera#e1$% Acetchoi!e#tera#e
Acetylcholinesterase enzymeAcetylcholinesterase enzyme
......
...
Nerve 1Nerve 1Nerve 2Nerve 2
SignalSignal
14.1 Role14.1 Role Hydrolysis and deactivation of acetylcholineHydrolysis and deactivation of acetylcholine
Prevents acetylcholine reactivating receptorPrevents acetylcholine reactivating receptor
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1$% Acetchoi!e#tera#e1$% Acetchoi!e#tera#e
activeactive inactiveinactive
14.2 Hydrolysis reaction catalysed14.2 Hydrolysis reaction catalysed
Acetylcholine
CH3
C
O
O
Choline
+ NMe3C
O
CH3 OH
Acetic acid
NMe3HO
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1$% Acetchoi!e#tera#e1$% Acetchoi!e#tera#e
Inhibitor blocks acetylcholinesteraseInhibitor blocks acetylcholinesterase Ach is unable to bindAch is unable to bind
Ach returns to receptor and reactivatesAch returns to receptor and reactivates
itit Enzyme inhibitor has the same effect asEnzyme inhibitor has the same effect as
a cholinergic agonista cholinergic agonist
22ooMessageMessage
Nerve 2Nerve 2
Enzyme inhibitorEnzyme inhibitor
(Anticholinesterase)(Anticholinesterase)14.3 Effect of inhibition14.3 Effect of inhibition
AchAch
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1$% Acetchoi!e#tera#e1$% Acetchoi!e#tera#e
14.4 Structure of enzyme complex14.4 Structure of enzyme complex
S
S
SS
S
S
S
S
S S
S
S
S
S
S S
S
S
Enzyme
EnzymeEnzyme
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::O
O
Serine
Histidine
Tyrosine
OH
N
N
HO
Aspartate
1$% Acetchoi!e#tera#e1$% Acetchoi!e#tera#e
14.5 Active site - binding interactions14.5 Active site - binding interactions
Anionic binding region similar to cholinergic receptor siteAnionic binding region similar to cholinergic receptor site Binding and induced fit strains Ach and weakens bondsBinding and induced fit strains Ach and weakens bonds Molecule positioned for reaction with His and SerMolecule positioned for reaction with His and Ser
vdwvdw
vdwvdw
hydrophobic
pockets
Anionic binding regionEster binding region
Me
N
CH2 CH2O
C
CH3
O
Me
Me
H-bondIonic
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1$% Acetchoi!e#tera#e1$% Acetchoi!e#tera#e
14.6 Active site - Mechanism of catalysis14.6 Active site - Mechanism of catalysis
O H NNH
:
Serine Histidine(Nucleophile) (Base)
:
CH3C
O
O CH2CH2NMe3
Histidine(Base catalyst)
::
NNH
O
O
R
C
O
CH3
H
:
Histidine
::
NNH
O
O
R
C
O
CH3
H
COR
O
CH3
O NNH
H
:
:
:
Histidine
Acid catalyst
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1$% Acetchoi!e#tera#e1$% Acetchoi!e#tera#e
14.6 Active site - Mechanism of catalysis14.6 Active site - Mechanism of catalysis
C
OR
O
CH3
O N
NH
H
:
:
:
Histidine
H2O
Histidine
NNH
OOH
CCH3
O
H:
ROH
CO
CH3
O N
NH
Histidine
_
H :
::
C
O
OHCH3
O NNH
Histidine
Basic catalyst
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1$% Acetchoi!e#tera#e1$% Acetchoi!e#tera#e
14.6 Active site - Mechanism of catalysis14.6 Active site - Mechanism of catalysis
C
O
OHCH3
O NNH
:::
: H:
Histidine(Acid catalyst)
_
H
:
Histidine
::
C
O
OHCH3
O NNH
C
O
OHCH3
O NNH
:
_
H :
::
Histidine
Basic catalyst
OHC
O
CH3
OH NNH
:
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1$% Acetchoi!e#tera#e1$% Acetchoi!e#tera#e
Serine and water are poor nucleophilesSerine and water are poor nucleophiles
Mechanism is aided by histidine acting as a basic catalystMechanism is aided by histidine acting as a basic catalyst
Choline and serine are poor leaving groupsCholine and serine are poor leaving groups
Leaving groups are aided by histidine acting as an acid catalystLeaving groups are aided by histidine acting as an acid catalyst
Very efficient - 100 x 10Very efficient - 100 x 1066faster than uncatalysed hydrolysisfaster than uncatalysed hydrolysis
Acetylcholine hydrolysed within 100Acetylcholine hydrolysed within 100 secs of reaching activesecs of reaching active
sitesite
An aspartate residue is also involved in the mechanismAn aspartate residue is also involved in the mechanism
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1$% Acetchoi!e#tera#e1$% Acetchoi!e#tera#e
The catalytic triadThe catalytic triad
An aspartate residue interacts with the imidazole ring ofAn aspartate residue interacts with the imidazole ring of
histidine to orientate and activate ithistidine to orientate and activate it
Serine Histidine
(Nucleophile) (Base)
O H
N
N
H
O
O
Aspartat
:
:::
:
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1'% A!tichoi!e#tera#e#1'% A!tichoi!e#tera#e#
Inhibitors of acetylcholinesterase enzymeInhibitors of acetylcholinesterase enzyme
Block hydrolysis of acetylcholineBlock hydrolysis of acetylcholine
Acetylcholine is able to reactivate cholinergic receptorAcetylcholine is able to reactivate cholinergic receptor
Same effect as a cholinergic agonistSame effect as a cholinergic agonist
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1'% A!tichoi!e#tera#e#1'% A!tichoi!e#tera#e#
15.1 Physostigmine15.1 Physostigmine
Natural product from the African calabar beanNatural product from the African calabar bean Carbamate is essential (equivalent to ester of Ach)Carbamate is essential (equivalent to ester of Ach)
Aromatic ring is importantAromatic ring is important Pyrrolidine N is important (ionised at blood pH)Pyrrolidine N is important (ionised at blood pH) Pyrrolidine N is equivalent to the quaternary nitrogen of AchPyrrolidine N is equivalent to the quaternary nitrogen of Ach
N N
MeOC
O
NMe
H
Me MeUrethane orCarbamate
Pyrrolidine N
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Physostigmine
O:N
NH
H
MeNH
C
O
OAr
15.2 Mechanism of action15.2 Mechanism of action
:
OArC
O
MeNH
O
NHN:
:
H
OArC
O
MeNH
O
NHNH
: :
O ArC
O
MeNH
O
NHN
: H
:
:
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O ArC
O
MeNH
O
NHN
: H
:
:
15.2 Mechanism of action15.2 Mechanism of action
Rate of hydrolysis slower by 40 x 10Rate of hydrolysis slower by 40 x 1066
Stable carbamoylintermediate
O H
NH:N
Hydrolysis
very slow
OC
O:N
NH
MeNH
-ArOH
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15.2 Mechanism of action15.2 Mechanism of action
Carbonyl group
'deactivated'
:
O
CON
Me
H:
::
NH
Me
CO
O
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15.3 Physostigmine analogues15.3 Physostigmine analogues
Simplified analogueSimplified analogue Susceptible to hydrolysisSusceptible to hydrolysis Crosses BBB as free baseCrosses BBB as free base
CNS side effectsCNS side effects
Fully ionisedFully ionised Cannot cross BBBCannot cross BBB No CNS side effectsNo CNS side effects
More stable toMore stable tohydrolysishydrolysis
ExtraExtra NN-methyl group-methyl group
increases stabilityincreases stability
MiotineMiotine
C
N
O
O
H
Me
Me
CH
NMe2
(ionised at blood pH)
NeostigmineNeostigmine
NMe3OMe
N
Me
C
O
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CN
O
OAr
H
Me
-
+
Me
N
H
COAr
O
OH
::
Me
N
H
C
OH
OMeNH2
+
CO2
Water
Hydrolysis mechanismsHydrolysis mechanisms
Possible mechanism 1Possible mechanism 1
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Me
N
H
COAr
O-H
CN O
Me MeNH2
+
CO2
Compare:
CN
O
OAr
Me
Me -Me
No hydrolysis
Too reactive
Hydrolysis mechanismsHydrolysis mechanisms
Possible mechanism 2Possible mechanism 2
CN
O
OH
H
MeHH22OO
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Myasthenia gravis (sometimes abbreviated MG; from the Greekmyastheneia,lit.'muscle disease', and Latingravis, 'serious') is a neuromuscular disease leading to
fluctuating muscle weakness and fatiguability. At about 14 cases per 100,000 (in theU.S.), it is one of the lesser known autoimmune disorders. Weakness is typicallycaused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of theneurotransmitter acetylcholine. Myasthenia is treated with immunosuppressants,cholinesterase inhibitors and, in selected cases, thymectomy.
Myasthenia gravis
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Treatment
Myasthenia gravis can usually be controlled with medication. Medication is used for twodifferent endpoints:
Direct improvement of the weakness
Reduction of the autoimmune process
Muscle function is improved by cholinesterase inhibitors, such as neostigmine andpyridostigmine. These slow the natural enzyme cholinesterase that degrades
acetylcholine in the motor end plate; the neurotransmitter is therefore around longerto stimulate its receptor. Usually doctors will start with a low dose, eg 3x20mgpyridostigmine, and increase until the desired result is achieved. If taken 30 minutesbefore a meal, symptoms will be mild during eating. Side effects, like perspirationand diarrhea can be countered by adding atropine. Pyridostigmine is a short-liveddrug with a half-life of about 4 hours.
NMe3OMe2N
O
Neostigmine
N
OMe 2N
O
Me
Pyridostigmine
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http://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?
fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable
)+&cid=HTDRUG
http://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?
fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable
)+&cid=HTDRUG
http://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUGhttp://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid=HTDRUG8/10/2019 Patrick Ch19 p3
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Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative diseasecharacterized by progressive cognitive deterioration together with declining activities of dailyliving and neuropsychiatric symptoms or behavioral changes. It is the most common type of
dementia.The most striking early symptom is loss of short term memory (amnesia), which usuallymanifests as minor forgetfulness that becomes steadily more pronounced with illnessprogression, with relative preservation of older memories. As the disorder progresses, cognitive(intellectual) impairment extends to the domains of language (aphasia), skilled movements(apraxia), recognition (agnosia), and those functions (such as decision-making and planning)closely related to the frontal and temporal lobes of the brain as they become disconnected from
the limbic system, reflecting extension of the underlying pathological process. These changesmake up the essential human qualities, and thus AD is sometimes described as a diseasewhere the victims suffer the loss of qualities that define human existence.This pathological process consists principally of neuronal loss or atrophy, principally in thetemporoparietal cortex, but also in the frontal cortex, together with an inflammatory response tothe deposition of amyloid plaques and neurofibrillary tangles.
Alzheimer's disease (AD)
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Acetylcholinesterase inhibitorsAcetylcholinesterase (AChE) inhibition was thought to be important because there is a reduction in activity
of the cholinergic neurons. AChE-inhibitors reduce the rate at which acetylcholine (ACh) is broken downand hence increase the concentration of ACh in the brain (combatting the loss of ACh caused by the deathof the cholinergin neurons). Acetylcholinesterase-inhibitors seemed to modestly moderate symptoms butdo not alter the course of the underlying dementing process.[67][68][69]Examples include:tacrine - no longer clinically useddonepezil - (marketed as Aricept)galantamine - (marketed as Razadyne in the U.S.A. Marketed as Reminyl or Nivalin in the rest of the world)rivastigmine - (marketed as Exelon)There is significant doubt as to the effectiveness of cholinesterase inhibitors. A number of recent articleshave criticized the design of studies reporting benefit from these drugs, concluding that they have doubtfulclinical utility, are costly, and confer many side effects.[70][71] The pharmaceutical companies, but alsosome independent clinicians, dispute the conclusions of these articles. A transdermal patch is underdevelopment that may ease administration of rivastigmine.[72]ivastigmine.
MeO
MeO
O
N
Donepezil (Aricept)
ON
O
Rivastigmine(Exelon, Novartis)
Me
Et
Me
NMe 2
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1'%$ Or"a!opho#phate#1'%$ Or"a!opho#phate#
a) Nerve gasesa) Nerve gases
Agents developed in World War 2Agents developed in World War 2
Agents irreversibly inhibit acetylcholinesteraseAgents irreversibly inhibit acetylcholinesterase Permanent activation of cholinergic receptors by AchPermanent activation of cholinergic receptors by Ach Results in deathResults in death
DyflosDyflos
(Diisopropyl fluorophosphonate)(Diisopropyl fluorophosphonate)
iPrO
P
O
FiPrO
SarinSarin
P
Me F
OiPrO
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NS
P
O
O
VX Nerve Agent
The VX nerve agent is the most well-known of the V-series of nerve agents. Its chemical nameis O-ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothiolate and its molecular formula isC11H26NO2PS.
The only countries known to possess VX are the United States and Russia. VX agent isconsidered an area denial weapon due to its physical properties.
With its high viscosity and low volatility VX has the texture and feel of high-grade motor oil. Thismakes it especially dangerous, as it has a high persistence in the environment. It is odorlessand tasteless, and can be distributed as a liquid or, through evaporation, into small amounts ofvapor. It works as a nerve agent by blocking the function of the enzyme acetylcholinesterase.
Normally, an electric nerve pulse would cause the release of acetylcholine over a synapse thatwould stimulate muscle contraction. The acetylcholine is then broken down to non-reactivesubstances (acetic acid and choline) by the acetylcholinesterase enzyme. If more muscletension is needed the nerve must release more acetylcholine. VX blocks the action ofacetylcholinesterase, thus resulting in sustained contractions of all the muscles in the body.Sustained contraction of the diaphragm muscle causes death by asphyxiation.
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Often regarded as the deadliest nerve agent created to date, as little as 200 micrograms is
enough to kill an average person, depending on method of absorption. Death can be avoided ifthe appropriate antidote is injected immediately after exposure. The most commonly usedantidote is atropine and pralidoxime, which is issued for military personnel in the form of anautoinjector. Standard chemical agent resistance pills are also effective. Atropine works bybinding and blocking a subset of acetylcholine receptors (known as muscarinic acetylcholinereceptor, mAchR), so that the build up of acetylcholine produced by loss of theacetylcholinesterase function can no longer affect their target. This prevents involuntary
muscle actions so that muscles like the diaphragm are not in constant contraction. Theinjection of pralidoxime regenerates bound acetylcholinesterase.
N
S
P
O
O
VX Nerve Agent
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The chemist Ranajit Ghosh discovered the V-series nerve agents at the government researchestablishment at Porton Down, England in 1952; VX was passed over in favour of continuing withsarin as their chemical weapon of choice. The United Kingdom unilaterally renounced chemical andbiological weapons in 1956. In 1958 the British government traded their research on VX technologywith the United States of America in exchange for information on thermonuclear weapons. The US
then went into production of large amounts of VX in 1961.
The US later destroyed all of its stockpiles of the deadly nerve agent (by incineration at JohnstonIsland in the South Pacific), as mandated by the US accession to the Chemical Weapons ConventionEarlier, pre-treaty disposal included the US Army's CHASE (Cut Holes And Sink 'Em) program, inwhich old ships were filled with chemical weapons stockpiles and then scuttled. CHASE 8 wasconducted on June 15, 1967, in which the S.S.Cpl. Eric G. Gibsonwas filled with 7,380 VX rockets
and scuttled in 7,200 feet of water, off the coast of Atlantic City, New Jersey. The long-termenvironmental ramifications of exposing large quantities of VX to seawater and marine life could posea grave danger, but are ultimately unknown.
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The US is also destroying chemical weapons stockpiles containing VX in nine other locations, one of whichis in Russia. On June 12, 2005, it was reported that more than 250,000 US gallons (950 m) of the chemical
weapon are stored at the Newport Chemical Depot in Newport, Indiana, about 30 miles (50 km) north ofTerre Haute, Indiana. The VX is in the process of being hydrolyzed to much less toxic byproducts usingconcentrated caustic solution. The VX hydrolysate produced will contain mainly a phosphonate ester and athiolamine, with 20 parts per billion or less of residual VX. (Interestingly, 20 ppb is the level of VX in waterthat is considered permissible for drinking by US combat troops.)
A plan was developed to truck the hydrolysate from Indiana to the DuPont Chambers Works SecureEnvironmental Facility at Deepwater, NJ where it was to be further treated to destroy the phosphonate esterand the thiolamine, and dumped into the Delaware River.[2] The governors of Delaware, New Jersey,Pennsylvania, and New York have opposed this plan and the New Jersey Governor Codey instructed theNew Jersey Department of Transportation to deny entry to any trucks carrying the hydrolysate to theDeepwater facility. Prior to the current plan, it had been proposed that the hydrolysate be dumped into theGreat Miami River, a tributary of the Ohio River, near Dayton, Ohio but the community there successfullydefeated the proposal.
VX hydrolysis began on May 5 2005 and as of June 12 the facility had destroyed 2,894 US gallons (11 m)of VX. A contained spill of 30 US gallons (100 L) drew attention to the disposal process, but authorities saidno agent was released and no one was injured in the spill.Iraq under Saddam Hussein admitted to UNSCOM that it had researched VX, but denied weaponizing theagent due to production failure. [1] Subsequent investigation after the 2003 Invasion of Iraq indicates thatIraq had indeed weaponized VX in 1988 and had dropped three VX-filled bombs on Iran. [2]
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1'%$ Or"a!opho#phate#1'%$ Or"a!opho#phate#
b) Mechanism of actionb) Mechanism of action
Irreversible phosphorylationIrreversible phosphorylation P-O bond very stableP-O bond very stable
PiPrO F
OiPrO
STABLE
-H
O
PO
iPrO
iPrO
Serine
OH
Serine
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c) Medicinal organophosphatec) Medicinal organophosphate
Used to treat glaucomaUsed to treat glaucoma Topical applicationTopical application Quaternary N is added to improve binding interactionsQuaternary N is added to improve binding interactions Results in better selectivity and lower, safer dosesResults in better selectivity and lower, safer doses
EcothiopateEcothiopateMe3N CH2 CH2 S P
O
OEt
OEt
1'%$ Or"a!opho#phate#1'%$ Or"a!opho#phate#
NS
P
O
O
VX Nerve Agent
h h
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d) Organophosphates as insecticidesd) Organophosphates as insecticides
Relatively harmless to mammalsRelatively harmless to mammals
Agents act as prodrugs in insectsAgents act as prodrugs in insects Metabolised by insects to produce a toxic metaboliteMetabolised by insects to produce a toxic metabolite
ParathionParathion
EtO
P
S
EtO O NO2
MalathionMalathion
CH
CH2CO2Et
CO2Et
S
P
MeO
SMeO
1'%$ Or"a!opho#phate#1'%$ Or"a!opho#phate#
O h h
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d) Organophosphates as insecticidesd) Organophosphates as insecticides
MAMMALS INSECTS
NO2O
P
EtO
SEtO
PARATHION
(Inactive Prodrug)Active drug
Phosphorylates enzyme
DEATHDEATH
Mammalian
Metabolism
EtO
P
S
EtO OH
INACTIVE
& excreted
EtO
P
O
EtO O NO2Insect
Oxidative
desulphurisation
1'%$ Or"a!opho#phate#1'%$ Or"a!opho#phate#
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N
N
O
POEt
S OEt
Diazinon
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http://www.physioviva.com/movies/neurotoxic_insecticides/index.html
N
N
Me
NCl
N NH
NNO2
Nicotine Imidacloprid
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e) Design of Organophosphate Antidotese) Design of Organophosphate Antidotes
Quaternary N is added to bind to the anionic regionQuaternary N is added to bind to the anionic region
Side chain is designed to place the hydroxylamine moiety inSide chain is designed to place the hydroxylamine moiety in
the correct position relative to phosphorylated serinethe correct position relative to phosphorylated serine
Pralidoxime 1 million times more effective thanPralidoxime 1 million times more effective than
hydroxylaminehydroxylamine
Cannot act in CNS due to charge - cannot cross bbbCannot act in CNS due to charge - cannot cross bbb
PralidoximePralidoximeN
CH3
CHN
OH
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e) Design of Organophosphate Antidotese) Design of Organophosphate Antidotes
H
N CHNO
H
Me Me
NO
PNCH
O
OR
OR
CO2 OHSER
Active Site (Free)
CO2 O
P
O OR
OR
SER
Active Site (Blocked)
1'%$ Or"a!opho#phate#1'%$ Or"a!opho#phate#
1' $ O h h t1' $ Or a!opho#phate#
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e) Design of Organophosphate Antidotese) Design of Organophosphate Antidotes
Prodrug for pralidoximeProdrug for pralidoxime Passes through BBB as free basePasses through BBB as free base
Oxidised in CNS to pralidoximeOxidised in CNS to pralidoxime
ProPAMProPAM
N
HH
CH3
NOH
1'%$ Or"a!opho#phate#1'%$ Or"a!opho#phate#
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Act in CNSAct in CNS
Must cross blood brain barrierMust cross blood brain barrier
Used to treat memory loss in Alzheimers diseaseUsed to treat memory loss in Alzheimers disease
Alzheimers causes deterioration of cholinergic receptors inAlzheimers causes deterioration of cholinergic receptors in
brainbrain
Smart drugs inhibit Ach hydrolysis to increase activity atSmart drugs inhibit Ach hydrolysis to increase activity atremaining receptorsremaining receptors
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N
EtNMe2
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Donepezil
Tacrine (Cognex)Toxic side effects
Rivastigmine (Exelon)
(analogue of physostigmine)
Galanthamine
(daffodil and snowdrop bulbs
Metrifonate
(organophosphate)
Xanomeline
Anabaseine
(ants and marine worms)
N
NH2
MeO
MeO
O
CH2 N
H
Cl
CH O
C
N
O
MeMe
MeOP CCl3
O
MeOOH
HN N
NMe
N
S
N
O Me
N
O
MeO
Me
HO
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Nootropics(from Greek, 'acting on the mind'), popularly referred to as "smart drugs", aresubstances which boost human cognitive abilities (the functions and capacities of the brain). Theword nootropic is derived from the Greek wordsnoosor "mind" andtropeinmeaning "to ward."Typically, nootropics are alleged to work by increasing the brain's supply of neurochemicals(neurotransmitters, enzymes, and hormones), by improving the brain's oxygen supply, or bystimulating nerve growth.
Most alleged nootropic substances are nutrients or plant components (herbs, roots, beans, bark,etc.), available over the counter at health food and grocery stores, and are used as nutritionalsupplements. Some nootropics are drugs, used to treat people with cognitive learning difficulties,neural degradation (Alzheimer's and Parkinson's), and for cases of oxygen deficit to preventhypoxia. These drugs have a variety of human enhancement applications as well, are marketedheavily on the World Wide Web, and are used by many people in personal cognitiveenhancement regimens.
With some nootropics the effects are subtle and gradual, such as with most nerve growthinducers, and may take weeks or even months before any cognitive improvement is noticed. Atthe other end of the spectrum are nootropics which have effects that are immediate, profound,and obvious. While scientific studies support some of the claimedbenefits, it is worth noting thatmany of the claims attributed to a variety of nootropics have not been formally tested.
Nootropics
Dementia
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Dementia
Definition
The term dementia refers to symptoms, including changes in memory, personality, and
behavior, that result from a change in the functioning of the brain. These declining changesare severe enough to impair the ability of a person to perform a function or to interact
socially. This operating definition encompasses 7080 different typesentia. They include
changes due to diseases (Alheimer!s and "reutfeld#$a%ob diseases&, changes due to a heart
attac% or repeated blo's to the head (as suffered by boers&, and damage due to long#term
alcohol abuse.
Dementia is not the same thing as delirium or mental retardation. Delirium is typically a briefstate of mental confusion often associated 'ith hallucinations. )ental retardation is a
condition that usually dates from childhood and is characteried by impaired intellectual
ability* mentally retarded individuals typically have + (intelligence -uotient& scores belo'
70 or 7.
Description
The absent#mindedness and confusion about familiar settings and tas%s that are hallmar%s of
dementia used to be considered as part of a typical aging pattern in the elderly. +ndeed,
dementia historically has been called senility. Dementia is no' recognied not to be a normal
part of aging. The symptoms of dementia can result from different causes. /ome of the
changes to the brain that cause dementia are treatable and can be reversed, 'hile other
changes are irreversible.
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Neurotransmitter support - supplying the body with the precursors and cofactors it needs toproduce neurotransmitters. Keeping the brain's neurotransmitters at high levels improvesconcentration, mental focus, calculation ability, memory encoding, recall, creativity, mood, andcures and prevents most depressions. The four main neurotransmitters are acetylcholine,dopamine, norepinephrine and serotonin.
Note that cardiovascular exercise performed on a regular basis also has nootropic effects, byincreasing the body's capacity to supply brain cells with oxygen. Exercise is highly synergisticwith nutritional supplementation, and a health regimen is incomplete without it.
hat ty$e of dr!gs 6ill enhance cognition7
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Cholinergics are substances which affect the neurotransmitter acetylcholine or the componentsof the nervous system which utilize acetylcholine. Acetylcholine facilitates memory,concentration, focus, and high-order thought processes (abstract thought, calculation,innovation, etc.). Increasing the availability of this neurotransmitter in the brain may improve
these functions and increase the duration in which they may be engaged without slowing downor stopping. Oversupplying the brain with acetylcholine may have the opposite effect,temporarily reducing rather than improving mental performance.
E l f Ch li i ; t i 0
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Acetyl-L-carnitine (ALCAR) - Amino acid. Precursor of
acetylcholine (donating the acetyl portion to the acetylcholine
molecule). It is synergistic with lipoic acid.
Centrophenoxine (Lucidril) - Drug. cholinergic agent, enhances
color perception.
Choline - precursor to acetylcholine (an essential component of the
acetylcholine molecule).Alpha-GPC (L-alpha glycerylphosphorylcholine, Choline
alfoscerate) - most effective choline precursor, readily crosses the
blood-brain barrier.
CDP-Choline (Cytidine Diphosphate Choline) - choline precursor,tends to be less expensive and similar in effect to Alpha GPC.
Choline bitartrate - precursor of acetylcholine, general nootropic,
anti-depressant.
Choline citrate - precursor of the neurotransmitter acetylcholine,
general nootropic, anti-depressant.
E%a#$les of Cholinergic ;ootro$ic 0r!gs
O
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N
O
NH2
Piracetam(brand name: Nootropil, Myocalm)
Piracetam (brand name: Nootropil, Myocalm), is a cerebral function regulating drug which is claimed to be able toenhance cognition as well as slow down brain aging. Piracetam's chemical name is 2-oxo-pyrrolidone, or 2-oxo-1-pyrrolidine acetamide. Piracetam is a cyclic derivative of GABA. It is one of the racetams, and is similar to the aminoacid pyroglutamate. Though rare in the United States, piracetam is commonly prescribed in Europe for a variety ofconditions.
Several meta-reviews of literature on piracetam indicate that piracetam increases performance on a variety of cognitivetasks among dyslexic children, though this may reflect its enhancement of cross-hemispheric communication and ofcognitive function in general, rather than a specific improvement in whatever causes dyslexia. Piracetam also seems toinhibit brain damage caused by a variety of factors including hypoxia and excessive alcohol consumption.[1][2]Piracetam has been studied in an extensive number of clinical experiments, and has shown positive results in thetreatment of post-stroke aphasia, epilepsy, cognitive decline following heart and brain surgery, dementia[3], andmyoclonus,[4][5]and some believe that understanding the mechanism through which it works can teach us about therole of inter-hemispheric communication in the brain.
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AphasiaDefinition
Aphasia is a communication disorder that occurs after language has been developed, usually
in adulthood. 5ot simply a speech disorder, aphasia can affect the ability to comprehend thespeech of others, as 'ell as the ability to read and 'rite. +n most instances, intelligence per
se is not affected.
Description
Aphasia has been %no'n since the time of the ancient 6ree%s. o'ever, it has been the focus
of scientific study only since the mid#nineteenth century. Although aphasia can be caused bya head inury and neurologic conditions, its most common cause is stro%e, a disruption of
blood flo' to the brain, 'hich affects brain metabolism in localied areas of the brain.
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)yoclonus
Definition
)yoclonus is a brief, rapid, shoc%#li%e er%ing movement.
Description
)yoclonus can be a symptom of a separate disorder, or can be the only or primary
neurological finding, in 'hich case it is termed essential myoclonus. )yoclonus may occur in
epilepsy, or follo'ing many different types of brain inury, such as lac% of oygen, stro%e,
trauma, or poisoning. )yoclonus can occur in one or more limbs, or may be generalied,involving much of the brain.
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Infarction
The process of anoic tissue death. The usual cause is occlusion of an artery by a
thrombus or embolus and sometimes by severe atherosclerosis.