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Title: Patrick


1
Patrick An Introduction to Medicinal Chemistry
3/e Chapter 19 CHOLINERGICS, ANTICHOLINERGICS
ANTICHOLINESTERASES Part 3 Cholinergics
anticholinesterases
2
Contents Part 3 Cholinergics
anticholinesterases 14. Acetylcholinesterase 14
.1. Role 14.2. Hydrolysis reaction
catalysed 14.3. Effect of inhibition 14.4. Str
ucture of enzyme complex 14.5. Active site -
binding interactions 14.6. Active site -
Mechanism of catalysis (3 slides) 15. Anticholines
terases 15.1. Physostigmine 15.2. Mechanism
of action (3 slides) 15.3. Physostigmine
analogues 15.4. Organophosphates (9
slides) 15.5. Anticholinesterases as Smart
Drugs (2 slides) 30 slides
3
14. Acetylcholinesterase
  • 14.1 Role
  • Hydrolysis and deactivation of acetylcholine
  • Prevents acetylcholine reactivating receptor

4
14. Acetylcholinesterase
14.2 Hydrolysis reaction catalysed
active
inactive
5
14. Acetylcholinesterase
14.3 Effect of inhibition
  • Inhibitor blocks acetylcholinesterase
  • Ach is unable to bind
  • Ach returns to receptor and reactivates it
  • Enzyme inhibitor has the same effect as a
    cholinergic agonist

6
14. Acetylcholinesterase
14.4 Structure of enzyme complex
7
14. Acetylcholinesterase
14.5 Active site - binding interactions
  • Anionic binding region similar to cholinergic
    receptor site
  • Binding and induced fit strains Ach and weakens
    bonds
  • Molecule positioned for reaction with His and Ser

8
14. Acetylcholinesterase
14.6 Active site - Mechanism of catalysis
Acid catalyst
9
14. Acetylcholinesterase
14.6 Active site - Mechanism of catalysis
Histidine Basic catalyst
10
14. Acetylcholinesterase
14.6 Active site - Mechanism of catalysis
11
14. Acetylcholinesterase
  • Serine and water are poor nucleophiles
  • Mechanism is aided by histidine acting as a basic
    catalyst
  • Choline and serine are poor leaving groups
  • Leaving groups are aided by histidine acting as
    an acid catalyst
  • Very efficient - 100 x 106 faster than
    uncatalysed hydrolysis
  • Acetylcholine hydrolysed within 100 msecs of
    reaching active site
  • An aspartate residue is also involved in the
    mechanism

12
14. Acetylcholinesterase
  • The catalytic triad
  • An aspartate residue interacts with the imidazole
    ring of histidine to orientate and activate it

13
15. Anticholinesterases
  • Inhibitors of acetylcholinesterase enzyme
  • Block hydrolysis of acetylcholine
  • Acetylcholine is able to reactivate cholinergic
    receptor
  • Same effect as a cholinergic agonist

14
15. Anticholinesterases
15.1 Physostigmine
  • Natural product from the African calabar bean
  • Carbamate is essential (equivalent to ester of
    Ach)
  • Aromatic ring is important
  • Pyrrolidine N is important (ionised at blood pH)
  • Pyrrolidine N is equivalent to the quaternary
    nitrogen of Ach

15
15.2 Mechanism of action
16
15.2 Mechanism of action
Stable carbamoyl intermediate
Rate of hydrolysis slower by 40 x 106
17
15.2 Mechanism of action
Carbonyl group 'deactivated'
18
15.3 Physostigmine analogues
(ionised at blood pH)
  • Fully ionised
  • Cannot cross BBB
  • No CNS side effects
  • More stable to hydrolysis
  • Extra N-methyl group increases stability
  • Simplified analogue
  • Susceptible to hydrolysis
  • Crosses BBB as free base
  • CNS side effects

19
Hydrolysis mechanisms
Possible mechanism 1
20
Hydrolysis mechanisms
Possible mechanism 2
Compare
21
Myasthenia gravis
Myasthenia gravis (sometimes abbreviated MG from
the Greek myastheneia, lit. 'muscle disease', and
Latin gravis, 'serious') is a neuromuscular
disease leading to fluctuating muscle weakness
and fatiguability. At about 14 cases per 100,000
(in the U.S.), it is one of the lesser known
autoimmune disorders. Weakness is typically
caused by circulating antibodies that block
acetylcholine receptors at the post-synaptic
neuromuscular junction, inhibiting the
stimulative effect of the neurotransmitter
acetylcholine. Myasthenia is treated with
immunosuppressants, cholinesterase inhibitors
and, in selected cases, thymectomy.
http//www.healcentral.org/healapp/showMetadata?me
tadataId3621
22
Treatment Myasthenia gravis can usually be
controlled with medication. Medication is used
for two different endpoints Direct improvement
of the weakness Reduction of the autoimmune
process Muscle function is improved by
cholinesterase inhibitors, such as neostigmine
and pyridostigmine. These slow the natural enzyme
cholinesterase that degrades acetylcholine in the
motor end plate the neurotransmitter is
therefore around longer to stimulate its
receptor. Usually doctors will start with a low
dose, eg 3x20mg pyridostigmine, and increase
until the desired result is achieved. If taken 30
minutes before a meal, symptoms will be mild
during eating. Side effects, like perspiration
and diarrhea can be countered by adding atropine.
Pyridostigmine is a short-lived drug with a
half-life of about 4 hours.
23
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owLfts.asp?fname04867titleNEOSTIGMINE(Injectio
n)(Injectable)cidHTDRUG
http//www.healthtouch.com/bin/EContent_HT/dnoteSh
owLfts.asp?fname04944titlePYRIDOSTIGMINE(Injec
tion)(Injectable)cidHTDRUG
24
Alzheimer's disease (AD)
Alzheimer's disease (AD), also known simply as
Alzheimer's, is a neurodegenerative disease
characterized by progressive cognitive
deterioration together with declining activities
of daily living 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 usually
manifests as minor forgetfulness that becomes
steadily more pronounced with illness
progression, 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 changes
make up the essential human qualities, and thus
AD is sometimes described as a disease where the
victims suffer the loss of qualities that define
human existence. This pathological process
consists principally of neuronal loss or atrophy,
principally in the temporoparietal cortex, but
also in the frontal cortex, together with an
inflammatory response to the deposition of
amyloid plaques and neurofibrillary tangles.
25
http//www.healthcentral.com/alzheimers/introducti
on-7-115.html
26
Acetylcholinesterase inhibitors Acetylcholinestera
se (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 down
and hence increase the concentration of ACh in
the brain (combatting the loss of ACh caused by
the death of the cholinergin neurons).
Acetylcholinesterase-inhibitors seemed to
modestly moderate symptoms but do not alter the
course of the underlying dementing
process.676869 Examples include tacrine -
no longer clinically used donepezil - (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 articles have criticized the
design of studies reporting benefit from these
drugs, concluding that they have doubtful
clinical utility, are costly, and confer many
side effects.7071 The pharmaceutical
companies, but also some independent clinicians,
dispute the conclusions of these articles. A
transdermal patch is under development that may
ease administration of rivastigmine.72ivastigmin
e.
27
15.4 Organophosphates
a) Nerve gases
  • Agents developed in World War 2
  • Agents irreversibly inhibit acetylcholinesterase
  • Permanent activation of cholinergic receptors by
    Ach
  • Results in death

28
The VX nerve agent is the most well-known of the
V-series of nerve agents. Its chemical name is
O-ethyl-S-2(diisopropylamino)ethyl
methylphosphonothiolate and its molecular formula
is C11H26NO2PS. The only countries known to
possess VX are the United States and Russia. VX
agent is considered 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. This makes it especially
dangerous, as it has a high persistence in the
environment. It is odorless and tasteless, and
can be distributed as a liquid or, through
evaporation, into small amounts of vapor. 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 that would stimulate
muscle contraction. The acetylcholine is then
broken down to non-reactive substances (acetic
acid and choline) by the acetylcholinesterase
enzyme. If more muscle tension is needed the
nerve must release more acetylcholine. VX blocks
the action of acetylcholinesterase, thus
resulting in sustained contractions of all the
muscles in the body. Sustained contraction of the
diaphragm muscle causes death by asphyxiation.
29
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 if the
appropriate antidote is injected immediately
after exposure. The most commonly used antidote
is atropine and pralidoxime, which is issued for
military personnel in the form of an
autoinjector. Standard chemical agent resistance
pills are also effective. Atropine works by
binding and blocking a subset of acetylcholine
receptors (known as muscarinic acetylcholine
receptor, mAchR), so that the build up of
acetylcholine produced by loss of the
acetylcholinesterase function can no longer
affect their target. This prevents involuntary
muscle actions so that muscles like the diaphragm
are not in constant contraction. The injection of
pralidoxime regenerates bound acetylcholinesterase
.
30
The chemist Ranajit Ghosh discovered the V-series
nerve agents at the government research
establishment at Porton Down, England in 1952 VX
was passed over in favour of continuing with
sarin as their chemical weapon of choice. The
United Kingdom unilaterally renounced chemical
and biological weapons in 1956. In 1958 the
British government traded their research on VX
technology with 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 Johnston Island
in the South Pacific), as mandated by the US
accession to the Chemical Weapons Convention.
Earlier, pre-treaty disposal included the US
Army's CHASE (Cut Holes And Sink 'Em) program, in
which old ships were filled with chemical weapons
stockpiles and then scuttled. CHASE 8 was
conducted on June 15, 1967, in which the S.S.
Cpl. Eric G. Gibson was filled with 7,380 VX
rockets and scuttled in 7,200 feet of water, off
the coast of Atlantic City, New Jersey. The
long-term environmental ramifications of exposing
large quantities of VX to seawater and marine
life could pose a grave danger, but are
ultimately unknown.
31
The US is also destroying chemical weapons
stockpiles containing VX in nine other locations,
one of which is in Russia. On June 12, 2005, it
was reported that more than 250,000 US gallons
(950 m³) of the chemical weapon are stored at the
Newport Chemical Depot in Newport, Indiana, about
30 miles (50 km) north of Terre Haute, Indiana.
The VX is in the process of being hydrolyzed to
much less toxic byproducts using concentrated
caustic solution. The VX hydrolysate produced
will contain mainly a phosphonate ester and a
thiolamine, with 20 parts per billion or less of
residual VX. (Interestingly, 20 ppb is the level
of VX in water that is considered permissible for
drinking by US combat troops.) A plan was
developed to truck the hydrolysate from Indiana
to the DuPont Chambers Works Secure Environmental
Facility at Deepwater, NJ where it was to be
further treated to destroy the phosphonate ester
and 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 the
New Jersey Department of Transportation to deny
entry to any trucks carrying the hydrolysate to
the Deepwater facility. Prior to the current
plan, it had been proposed that the hydrolysate
be dumped into the Great Miami River, a tributary
of the Ohio River, near Dayton, Ohio but the
community there successfully defeated the
proposal. VX hydrolysis began on May 5 2005 and
as of June 12 the facility had destroyed 2,894 US
gallons (11 m³) of VX. A contained spill of 30 US
gallons (100 L) drew attention to the disposal
process, but authorities said no 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 the agent due to production failure.
1 Subsequent investigation after the 2003
Invasion of Iraq indicates that Iraq had indeed
weaponized VX in 1988 and had dropped three
VX-filled bombs on Iran. 2
32
15.4 Organophosphates
b) Mechanism of action
STABLE
  • Irreversible phosphorylation
  • P-O bond very stable

33
15.4 Organophosphates
c) Medicinal organophosphate
  • Used to treat glaucoma
  • Topical application
  • Quaternary N is added to improve binding
    interactions
  • Results in better selectivity and lower, safer
    doses

34
15.4 Organophosphates
d) Organophosphates as insecticides
  • Relatively harmless to mammals
  • Agents act as prodrugs in insects
  • Metabolised by insects to produce a toxic
    metabolite

35
15.4 Organophosphates
d) Organophosphates as insecticides
Active drug
INACTIVE excreted
36
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37
http//www.physioviva.com/movies/neurotoxic_insect
icides/index.html
38
15.4 Organophosphates
e) Design of Organophosphate Antidotes
  • Strategy
  • Strong nucleophile required to cleave strong P-O
    bond
  • Find suitable nucleophile capable of cleaving
    phosphate esters
  • Water is too weak as a nucleophile
  • Hydoxylamine is a stronger nucleophile
  • Hydroxylamine is too toxic for clinical use
  • Increase selectivity by increasing binding
    interactions with active site

39
15.4 Organophosphates
e) Design of Organophosphate Antidotes
  • Quaternary N is added to bind to the anionic
    region
  • Side chain is designed to place the hydroxylamine
    moiety in the correct position relative to
    phosphorylated serine
  • Pralidoxime 1 million times more effective than
    hydroxylamine
  • Cannot act in CNS due to charge - cannot cross bbb

40
15.4 Organophosphates
e) Design of Organophosphate Antidotes
41
15.4 Organophosphates
e) Design of Organophosphate Antidotes
  • Prodrug for pralidoxime
  • Passes through BBB as free base
  • Oxidised in CNS to pralidoxime

42
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43
15.5 Anticholinesterases as Smart Drugs
  • Act in CNS
  • Must cross blood brain barrier
  • Used to treat memory loss in Alzheimers disease
  • Alzheimers causes deterioration of cholinergic
    receptors in brain
  • Smart drugs inhibit Ach hydrolysis to increase
    activity at remaining receptors

44
15.5 Anticholinesterases as Smart Drugs
45
Nootropics
Nootropics (from Greek, 'acting on the mind'),
popularly referred to as "smart drugs", are
substances which boost human cognitive abilities
(the functions and capacities of the brain). The
word nootropic is derived from the Greek words
noos or "mind" and tropein meaning "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 by
stimulating 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 nutritional supplements. 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 prevent hypoxia.
These drugs have a variety of human enhancement
applications as well, are marketed heavily on the
World Wide Web, and are used by many people in
personal cognitive enhancement regimens. With
some nootropics the effects are subtle and
gradual, such as with most nerve growth inducers,
and may take weeks or even months before any
cognitive improvement is noticed. At the other
end of the spectrum are nootropics which have
effects that are immediate, profound, and
obvious. While scientific studies support some of
the claimed benefits, it is worth noting that
many of the claims attributed to a variety of
nootropics have not been formally tested.
46
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 changes are 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 (Alzheimer's and
Creutzfeld-Jakob diseases), changes due to a
heart attack or repeated blows to the head (as
suffered by boxers), and damage due to long-term
alcohol abuse. Dementia is not the same thing as
delirium or mental retardation. Delirium is
typically a brief state of mental confusion often
associated with hallucinations. Mental
retardation is a condition that usually dates
from childhood and is characterized by impaired
intellectual ability mentally retarded
individuals typically have IQ (intelligence
quotient) scores below 70 or 75. Description The
absent-mindedness and confusion about familiar
settings and tasks that are hallmarks of dementia
used to be considered as part of a typical aging
pattern in the elderly. Indeed, dementia
historically has been called senility. Dementia
is now recognized not to be a normal part of
aging. The symptoms of dementia can result from
different causes. Some of the changes to the
brain that cause dementia are treatable and can
be reversed, while other changes are irreversible.
47
The elderly are most prone to dementia,
particularly those at risk for a stroke. The
historical tendency of women to live longer than
men has produced a higher prevalence of dementia
in older women. However, women and men are
equally prone to dementia. Over age 80, more than
20 of people have at least a mild form of
dementia. Dementia is especially prominent in
older people. The three main irreversible causes
are Alzheimer's disease, dementia with Lewy
bodies, and multi-infarct dementia (also called
vascular dementia).
48
What type of drugs will enhance cognition?
Neurotransmitter support - supplying the body
with the precursors and cofactors it needs to
produce neurotransmitters. Keeping the brain's
neurotransmitters at high levels improves
concentration, mental focus, calculation ability,
memory encoding, recall, creativity, mood, and
cures 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, by
increasing the body's capacity to supply brain
cells with oxygen. Exercise is highly synergistic
with nutritional supplementation, and a health
regimen is incomplete without it.
49
Cholinergics are substances which affect the
neurotransmitter acetylcholine or the components
of 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 down or
stopping. Oversupplying the brain with
acetylcholine may have the opposite effect,
temporarily reducing rather than improving mental
performance.
50
Examples of Cholinergic Nootropic Drugs
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. DMAE - approved
treatment for ADD/ADHD, precursor of
acetylcholine, cholinergic agent, removes
lipofuscin from the brain, anti-depressant. Huperz
ine A - potent acetylcholinesterase inhibitor
derived from Chinese club-moss. Lecithin -
precursor of acetylcholine. Pyrrolidone
derivatives Piracetam (Nootropil) - Prescription
drug (in Europe). The original (first)2, and
most commonly taken3 nootropic drug. It is a
cholinergic agent, synergistic with DMAE,
centrophenoxine, choline, and Hydergine.
Increases brain cell metabolism and energy
levels4, and speeds up interhemispheric flow of
information (left-right brain hemisphere
communication). Increases vigilance,5, improves
concentration, and enhances memory. Protects
neurons from hypoxia,2 and stimulates growth of
acetylcholine receptors. May also cause nerves to
regenerate. Piracetam markedly decreases the
formation of neuronal lipofuscin.6 It improves
posture in elderly people.7 It is not regulated
in the US. Aniracetam - Drug. Analog of
piracetam, and 4 to 8 times more potent. Like
piracetam, aniracetam protects against some
memory impairing chemicals, such as
diethyldithiocarbamate and clonidine.8 Also
like piracetam, aniracetam may enhance memory in
aging adults by increasing levels of brain
biogenic monoamines, which are beneficial to
learning and memory.1 Both racetams have
possible therapeutic use in treating fetal
alcohol syndrome.9 Aniracetam increases
vigilance.5 Etiracetam - It increases
vigilance.5 Nefiracetam - Drug. Analog of
piracetam, and facilitates hippocampal
neurotransmission.10 Oxiracetam - Drug. Analog
of piracetam, and 2 to 4 times stronger. Improves
memory, concentration, and vigilance. When fed to
pregnant rats, the offspring of those rats were
more intelligent than the offspring of rats fed a
saline solution placebo. Pramiracetam - Drug.
Fifteen times stronger than piracetam, of which
it is an analog.it is an analog.
51
Piracetam (brand name Nootropil, Myocalm), is
a cerebral function regulating drug which is
claimed to be able to enhance 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 amino acid pyroglutamate. Though rare in
the United States, piracetam is commonly
prescribed in Europe for a variety of conditions.
Several meta-reviews of literature on piracetam
indicate that piracetam increases performance on
a variety of cognitive tasks among dyslexic
children, though this may reflect its enhancement
of cross-hemispheric communication and of
cognitive function in general, rather than a
specific improvement in whatever causes dyslexia.
Piracetam also seems to inhibit 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 the treatment of post-stroke
aphasia, epilepsy, cognitive decline following
heart and brain surgery, dementia3, and
myoclonus,4 5and some believe that
understanding the mechanism through which it
works can teach us about the role of
inter-hemispheric communication in the brain.
52
Aphasia Definition Aphasia is a communication
disorder that occurs after language has been
developed, usually in adulthood. Not simply a
speech disorder, aphasia can affect the ability
to comprehend the speech of others, as well as
the ability to read and write. In most instances,
intelligence per se is not affected. Description
Aphasia has been known since the time of the
ancient Greeks. However, it has been the focus of
scientific study only since the mid-nineteenth
century. Although aphasia can be caused by a head
injury and neurologic conditions, its most common
cause is stroke, a disruption of blood flow to
the brain, which affects brain metabolism in
localized areas of the brain.
53
Myoclonus Definition Myoclonus is a brief,
rapid, shock-like jerking movement. Description
Myoclonus can be a symptom of a separate
disorder, or can be the only or primary
neurological finding, in which case it is termed
"essential myoclonus." Myoclonus may occur in
epilepsy, or following many different types of
brain injury, such as lack of oxygen, stroke,
trauma, or poisoning. Myoclonus can occur in one
or more limbs, or may be generalized, involving
much of the brain.
54
Infarction The process of anoxic tissue death.
The usual cause is occlusion of an artery by a
thrombus or embolus and sometimes by severe
atherosclerosis.
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