Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 19
CHOLINERGICS, ANTICHOLINERGICS
& ANTICHOLINESTERASES
Part 3: Cholinergics & anticholinesterases
©1
Contents
Part 3: Cholinergics & anticholinesterases
14. Acetylcholinesterase
14.1.
Role
14.2.
Hydrolysis reaction catalysed
14.3.
Effect of inhibition
14.4.
Structure of enzyme complex
14.5.
Active site - binding interactions
14.6.
Active site - Mechanism of catalysis (3 slides)
15. Anticholinesterases
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]
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14. Acetylcholinesterase
14.1 Role
• Hydrolysis and deactivation of acetylcholine
• Prevents acetylcholine reactivating receptor
...
Nerve 1
Signal
...
Nerve 2
...
Acetylcholinesterase enzyme
©1
14. Acetylcholinesterase
14.2 Hydrolysis reaction catalysed
O
O
C
CH3
O
CH3
Acetylcholine
active
HO
C
NMe3
OH
+
NMe3
Choline
Acetic acid
inactive
©1
14. Acetylcholinesterase
Enzyme inhibitor
(Anticholinesterase)
14.3 Effect of inhibition
2o Message
Ach
•
•
•
•
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
Nerve 2
©1
14. Acetylcholinesterase
14.4 Structure of enzyme complex
S
S
Enzyme
S
S
S
Enzyme
S
S
S
S
S
S
S
S
S
S
S
S
Enzyme
S
©1
14. Acetylcholinesterase
14.5 Active site - binding interactions
Ester binding region
Anionic binding region
Serine
OH
Aspartate
Histidine
N
hydrophobic
pockets
:
vdw
:O:
Me
N
Ionic
C
N
O
CH2
CH2
O
O
H-bond
H
CH3
O
vdwMe
Me
Tyrosine
•
•
•
Anionic binding region similar to cholinergic receptor site
Binding and induced fit strains Ach and weakens bonds
©1
Molecule positioned for reaction with His and Ser
14. Acetylcholinesterase
14.6 Active site - Mechanism of catalysis
O
O
:O :
CH2CH2NMe3
:N
:
:O
C
:
CH3
H
CH3
NH
C
R
O
:N
O
NH
H
Se rine
(Nucle ophile)
His tidine
(Ba se cata lys t)
:
: O:
His tidin e
(Ba s e)
C
O
:
CH3
:O :
R
CH3
O
C
OR
NH
H N
O
:N
NH
H
Histidine
Acid catalyst
Histidine
©1
14. Acetylcholinesterase
14.6 Active site - Mechanism of catalysis
H2O
ROH
:
:O :
CH3
O
C
OR
:N
O
NH
CH3
C
N
O
H
NH
Histidine
Histidine
_
:
: O:
O
CH3
C
H
O
::
O
NH
:N
CH3
C
O
OH
H
NH
:N
H
His tidine
Histidine
Basic catalyst
©1
14. Acetylcholinesterase
14.6 Active site - Mechanism of catalysis
_
:
:O :
:O :
CH3
C
CH3
OH
O
H
NH
C
OH
NH
:O :
:N
H
N
Histidine
Basic catalyst
Histidine
(Acid catalyst)
_
:
:O :
CH3
C
O
OH
NH
:N
O
CH3
C
OH
OH
:N
NH
H
His tidine
©1
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
©1
14. Acetylcholinesterase
The catalytic triad
•
An aspartate residue interacts with the imidazole ring of
histidine to orientate and activate it
:
:
:O
H
:N
:
H
:O:
N
O
Serine
(Nucleophile)
Histidine
(Base)
Aspartate
©1
15. Anticholinesterases
•
Inhibitors of acetylcholinesterase enzyme
•
Block hydrolysis of acetylcholine
•
Acetylcholine is able to reactivate cholinergic receptor
•
Same effect as a cholinergic agonist
©1
15. Anticholinesterases
15.1 Physostigmine
O
C O
Me
N
H
Urethane
or
Carbamate
•
•
•
•
•
Me
N
N
Me
Me
Pyrrolidine N
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
©1
: :
15.2 Mechanism of action
O
MeNH
H
H
O
:N
NH
MeNH
O Ar
C O
:N
Ar
NH
:O :
:
C
O
Physostigmine
O
:O :
Ar
N
NH
MeNH
C
:O :
:N
O Ar
NH
H
:
: :
C O
:
MeNH
O
H
©1
15.2 Mechanism of action
-ArOH
O
MeNH
C
O Ar
O
:N
NH
C
MeNH
H
O
:
:O :
:N
Stable carbamoyl
intermediate
O
Hydrolysis
very slow
H
:N
NH
Rate of hydrolysis slower by 40 x 106
©1
NH
15.2 Mechanism of action
O
O
H
H
C
N
Me
O
C
N
O
Me
Carbonyl group
'deactivated'
©1
15.3 Physostigmine analogues
Me
O
C
Me
O
CH
NMe2
N
H
•
•
•
•
O
Me
C
O
NMe3
N
Me
(ionised at blood pH)
Miotine
Neostigmine
Simplified analogue
Susceptible to hydrolysis
Crosses BBB as free base
CNS side effects
•
•
•
•
•
Fully ionised
Cannot cross BBB
No CNS side effects
More stable to
hydrolysis
Extra N-methyl group
increases stability
©1
Hydrolysis mechanisms
Possible mechanism 1
N
:
Me
 -O
+C
: O:
Me
N
OAr
H
Water
H
O
C
Me
N
OH
C
OAr
OH
MeNH2
+
CO 2
H
©1
Hydrolysis mechanisms
Possible mechanism 2
O
Me
-H
C
N
H2O
Me
N
OAr
C
O
MeNH2
+
CO 2
Me
C
O
N
OH
H
H
Too reactive
Compare:
O
Me
-Me
No hydrolysis
C
N
OAr
Me
©1
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 postsynaptic 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/showMe
tadata?metadataId=3621
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Me2N
Me2N
O
O
NMe3
O
O
N
Me
Neostigmine
Pyridostigmine
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.
©1
http://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?f
name=04867&title=NEOSTIGMINE+(Injection)+(Injectable)+&cid
=HTDRUG
http://www.healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp?fna
me=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable)+&cid=
HTDRUG
©1
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.
©1
http://www.healthcentral.com/alzheimers/introduction-7-115.html
©1
NMe2
Et
O
MeO
N
O
Me
Me
O
MeO
Donepezil (Aricept)
N
Rivastigmine
(Exelon, Novartis)
Acetylcholinesterase inhibitors
Acetylcholinesterase (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.[67][68][69]
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.[70][71] 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.[72]ivastigmine.
©1
15.4 Organophosphates
a) Nerve gases
iPrO
O
iPrO
P
iPrO
P
F
Dyflos
(Diisopropyl fluorophosphonate)
•
•
•
•
O
Me
F
Sarin
Agents developed in World War 2
Agents irreversibly inhibit acetylcholinesterase
Permanent activation of cholinergic receptors by Ach
Results in death
©1
O
P
N
O
S
VX Nerve Agent
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.
©1
O
P
N
O
S
VX Nerve Agent
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.
©1
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.
©1
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]
©1
15.4 Organophosphates
b) Mechanism of action
-H
Serine
Serine
H
O
O
iPrO
iPrO
O
P
iPrO
•
•
F
P
O
iPrO
STABLE
Irreversible phosphorylation
P-O bond very stable
©1
15.4 Organophosphates
c) Medicinal organophosphate
O
Me 3N
CH2
CH2
S
P
OEt
Ecothiopate
OEt
•
•
•
•
Used to treat glaucoma
Topical application
Quaternary N is added to improve binding interactions
Results in better selectivity and lower, safer doses
O
P
N
O
S
VX Nerve Agent
©1
15.4 Organophosphates
d) Organophosphates as insecticides
EtO
MeO
S
CO2Et
P
P
EtO
S
O
NO2
MeO
S
CH
CH2 CO2Et
Parathion
•
•
•
Malathion
Relatively harmless to mammals
Agents act as prodrugs in insects
Metabolised by insects to produce a toxic metabolite
©1
15.4 Organophosphates
d) Organophosphates as insecticides
MAMMALS
EtO
INSECTS
S
EtO
P
EtO
O
P
O
NO2
PARATHION
(Inactive Prodrug)
Insect
Oxidative
desulphurisation
EtO
O
NO2
Active drug
Mammalian
Metabolism
EtO
S
Phosphorylates enzyme
P
EtO
OH
INACTIVE
& excreted
DEATH
©1
S
N
N
OEt
P
O
OEt
Diazinon
©1
http://www.physioviva.com/movies/neurotoxic_insecticides/index.html
N
N
N
NO2
NH
Me
N
Nicotine
Cl
N
Imidacloprid
©1
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
O
O
NH 2OH + RO P OR
Hydroxylamine
•
•
OR
O P OR
H2 N
+
ROH
OR
Hydroxylamine is too toxic for clinical use
Increase selectivity by increasing binding interactions with active
site
©1
15.4 Organophosphates
e) Design of Organophosphate Antidotes
Pralidoxime
N
CH3
•
•
•
•
CH N
OH
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
©1
15.4 Organophosphates
e) Design of Organophosphate Antidotes
O
N
CH N
N
H
O
O
Me
CH N
Me
O
P
OR
OR
OR
P
OR
CO 2
H
Active Site (Blocked)
O
CO 2
OH
SER
SER
Active Site (Free)
©1
15.4 Organophosphates
e) Design of Organophosphate Antidotes
H
H
ProPAM
NOH
N
CH3
•
•
•
Prodrug for pralidoxime
Passes through BBB as free base
Oxidised in CNS to pralidoxime
©1
http://www.superstock.com/ImagePreview/1245-W477
©1
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
©1
NMe2
15.5 Anticholinesterases as ‘Smart Drugs’ Me
Et
CH
O
N
C
Me
O
Cl
O
MeO
NH2
CH2
Rivastigmine (Exelon)
(analogue of physostigmine)
N
H
MeO
Donepezil
H
N
N
Tacrine (Cognex)
Toxic side effects
O
P
MeO
MeO
HO
Anabaseine
(ants and marine worms)
CCl3
OH
Metrifonate
(organophosphate)
O
MeO
N
S
N
N
N
Galanthamine
(daffodil and snowdrop bulbs
Me
O
Me
N
Me
Xanomeline
©1
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.
©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 changes
are severe enough to impair the ability of a person to perform a function or to interact
socially. This operating definition encompasses 70–80 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.
©
1
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).
©1
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.
©1
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.
©1
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.
Huperzine 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 taken[3] nootropic drug. It
is a cholinergic agent, synergistic with DMAE, centrophenoxine, choline, and Hydergine. Increases brain cell metabolism and
energy levels[4], 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.
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O
NH2
N
O
Piracetam (brand name: Nootropil®, Myocalm®)
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-1pyrrolidine 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, dementia[3], and
myoclonus,[4] [5]and some believe that understanding the mechanism through which it works can teach us about the
role of inter-hemispheric communication in the brain.
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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.
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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.
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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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