Patrick Ch19 p3

8/10/2019 Patrick Ch19 p3

1/54


2/54


3/54

1

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


4/54

1


activeactive inactiveinactive

14.2 Hydrolysis reaction catalysed14.2 Hydrolysis reaction catalysed

Acetylcholine

CH3

C

O

O

Choline

+ NMe3C

O

CH3 OH

Acetic acid

NMe3HO


5/54

1


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


6/54

1


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


7/54

1

::O

O

Serine

Histidine

Tyrosine

OH

N

N

HO

Aspartate


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


8/54

1


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


9/54

1



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


10/54

1



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

:


11/54

1


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


12/54

1


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

:

:::

:


13/54

1

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


14/54

1

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


15/54

1

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

:

:


16/54

1

O ArC

O

MeNH

O

NHN

: H

:

:


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


17/54

1


Carbonyl group

'deactivated'

:

O

CON

Me

H:

::

NH

Me

CO

O


18/54

1

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


19/54

1

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


20/54

1

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


21/54

1

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

htt$:55666.healcentral.

org5heala$$5sho6*etadata7

#etadata8d93)21
http://www.healcentral.org/healapp/showMetadata?metadataId=3621http://www.healcentral.org/healapp/showMetadata?metadataId=3621http://www.healcentral.org/healapp/showMetadata?metadataId=3621http://www.healcentral.org/healapp/showMetadata?metadataId=3621http://www.healcentral.org/healapp/showMetadata?metadataId=3621http://www.healcentral.org/healapp/showMetadata?metadataId=3621http://www.healcentral.org/healapp/showMetadata?metadataId=3621http://www.healcentral.org/healapp/showMetadata?metadataId=3621http://www.healcentral.org/healapp/showMetadata?metadataId=3621


22/54

1

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


23/54

1

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=HTDRUG


24/54

1

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)


25/54


26/54

1

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


27/54

1

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


28/54

1

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.


29/54

1

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


30/54

1

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.


31/54

1

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]


32/54

1


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


33/54

1

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


NS

P

O

O

VX Nerve Agent

h h


34/54

1

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


O h h


35/54

1

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



36/54

1

N

N

O

POEt

S OEt

Diazinon


37/54

1

http://www.physioviva.com/movies/neurotoxic_insecticides/index.html

N

N

Me

NCl

N NH

NNO2

Nicotine Imidacloprid
http://www.physioviva.com/movies/neurotoxic_insecticides/index.htmlhttp://www.physioviva.com/movies/neurotoxic_insecticides/index.htmlhttp://www.physioviva.com/movies/neurotoxic_insecticides/index.htmlhttp://www.physioviva.com/movies/neurotoxic_insecticides/index.htmlhttp://www.physioviva.com/movies/neurotoxic_insecticides/index.htmlhttp://www.physioviva.com/movies/neurotoxic_insecticides/index.html


38/54

1' $ O h h t1' $ O h h t


39/54

1

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


1' $ O h h t1' $ O h h t


40/54

1


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' $ O h h t1' $ Or a!opho#phate#


41/54

1


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



42/54

1

http://www.superstock.com/ImagePreview/1245-W477

1' ' A!tichoi!e#tera#e# a# (S)art *r "#1' ' A!tichoi!e#tera#e# a# (S)art *r+"#
http://www.superstock.com/ImagePreview/1245-W477http://www.superstock.com/ImagePreview/1245-W477http://www.superstock.com/ImagePreview/1245-W477http://www.superstock.com/ImagePreview/1245-W477


43/54

1

1'%' A!tichoi!e#tera#e# a# (S)art *r+"#1'%' A!tichoi!e#tera#e# a# (S)art *r+"#

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

1' ' A!tichoi!e#tera#e# a# (S)art *r+"#1' ' A!tichoi!e#tera#e# a# (S)art *r+"#CH O

N

EtNMe2


44/54

1

1'%' A!tichoi!e#tera#e# a# (S)art *r+"#1'%' A!tichoi!e#tera#e# a# (S)art *r+"#

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


45/54

1

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


46/54

1

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.


47/54


48/54

1

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


49/54

1

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


50/54

1

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


51/54

1

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.


52/54

1

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.


53/54

1

)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.


54/54

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.

Documents

Patrick Ch19 p3