Tourette Updates July Editors Question and Answers

Comments on Mecamylamine


Hi,
I am on your mailing list, and look forward reading it each time I
receive it. I feel compelled to write to you in reference to this
article on the Mecamylamine studies at USF. I have three children
with TS and BP. Though my children have not been part of the
studies, their physician is associated with USF. My children, twins
ages 13 and a daughter 8, have all been have been prescribed
Mecamylamine for TS and BP over the last three years. It has changed
our lives. I personally believe this to be a miracle drug. Also, my
one son had some side effects from the Inversine, so instead he uses
a Nicotine Patch. The patch also amazingly has the same results.
There is no doubt in My mind that inhibiting nicotinic receptors in
the brain is a major key to treating both TS and BP.
Knowing the changes this has brought into our lives I don't
understand why there isn't more articles written on the Mecamylamine
studies.

Just wanted to thank you for your newsletter.
Alison

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Hi Paul. In reading about mecamylamine I have a question you may be
able to help me with. It says they believe this drug may help
because it blocks actylcholine to the brain (or something of the
sort). I recently have been looking into supplementing with choline
or lecithin because of all the benefits it is suppose to have on
mood, the brain, behavior, and possibel movement disorders
etc...This is opposite of what this says- correct?? Am I correct in
it is saying actylcholine is an excitatory substance in the brain?
Thanks for any help. Laura


Hello Laura,

Thank you for contacting me. This is the best I can answer you at
the moment, as I am on my way out, however I would say that your
assumption is not accurate in context that you are looking for it
in. The following information will help you understand.
Acetylcholine is a neurotransmitter and the supplementing with
choline or lecithin is not opposite or as I understand your
questions apposing acetylcholine. See Below.

###########

acetylcholine


(esetelko´len) , a small organic molecule liberated at nerve endings
as a neurotransmitter . It is particularly important in the
stimulation of muscle tissue. The transmission of an impulse to the
end of the nerve causes it to release neurotransmitter molecules
onto the surface of the next cell, stimulating it. After such
release, the acetylcholine is quickly broken into acetate and
choline, which pass back to the first cell to be recycled into
acetylcholine again. The poison curare acts by blocking the
transmission of acetylcholine. Some nerve gases operate by
preventing the breakdown of acetylcholine causing continual
stimulation of the receptor cells, which leads to intense spasms of
the muscles, including the heart. Acetylcholine is often abbreviated
as Ach. See nervous system.

###########

In depth information about:
ACETYLCHOLINE & ACETYLCHOLINE RECEPTORS (AChRs)

http://www.neuro.wustl.edu/neuromuscular/mother/acetylcholine.htm


http://www.neurosci.pharm.utoledo.edu/MBC3320/acetylcholine.htm
The first neurotransmitter system to be covered will be the
cholinergic system. Acetylcholine was one of the first
neurotransmitters to be discovered, (originally
called "vagusschtuff" because it was found to be the substance
released by stimulation of the vagus nerve that altered heart muscle
contractions).

Acetylcholine is produced by the synthetic enzyme choline
acetyltransferase which uses acetyl coenzyme A and choline as
substrates for the formation of acetylcholine. Dietary choline and
phosphatidylcholine serve as the sources of free choline for
acetylcholine synthesis. Upon release, acetylcholine is metabolized
into choline and acetate by acetylcholinesterase, and other
nonspecific esterases. Acetylcholine release can be excitatory or
inhibitory depending on the type of tissue and the nature of the
receptor with which it interacts.
Cholinergic receptors can be divided into two types, muscarinic and
nicotinic, based on the pharmacological action of various agonists
and antagonists. Muscarinic receptors originally were distinguished
from nicotinic receptors by the selectivity of the agonists
muscarine and nicotine respectively. Muscarinic receptors will be
discussed in detail later, while nicotinic receptors will be
discussed in the next section.
Nicotinic cholinergic receptors
Nicotinic receptors produce pharmacologically and physiologically
distinct responses from muscarinic receptors, although acetylcholine
(and other agonists such as carbamylcholine) stimulates each type of
response. Nicotinic responses are of fast onset, short duration and
excitatory in nature. The pharmacology of nicotinic receptors has
been studied in great detail and our understanding of how ion
channel-coupled neurotransmitter receptors work is based largely on
the study of this class of proteins.
Nicotinic receptors are found in a variety of tissues, including the
autonomic nervous system, the neuromuscular junction and the brain
in vertebrates. They also are found in high quantities in the
electric organs of various electric eels and rays. The high
quantities of receptors in these tissues and the use of neurotoxins
from snake venom (e.g., cobra venom) that bind specifically to the
nicotinic receptor aided the purification of the receptor protein.
Agonists such as acetylcholine, carbamylcholine and nicotine produce
the physiological responses associated with nicotinic cholinergic
activation. Acetylcholine produces an influx of sodium through a
ligand-gated ion channel. Acetylcholine and carbamylcholine also
stimulate muscarinic receptors and therefore should be considered
mixed cholinergic agonists.
The amino acid sequence for the nicotinic receptor was determined
after solubilization of the receptor from the electric organ of
Torpedo californica using anionic detergents such as sodium dodecyl
sulfate, passing the receptor through an affinity column containing
 bungarotoxin (from snake venom) and washing the receptor from the =

column. Subsequently, molecular biological techniques were used to
clone additional receptor subunits. The nicotinic receptor consists
of five polypeptide subunits. The amino acid sequence for the 
subunits consists of a glycolipid region (which contains the ACh
binding site and a sulfhydryl groups) with four hydrophobic regions
that span the membrane. Nine  subunits have been cloned, along with=

four  subunits. In the neuromuscular junction,  and &#61543=
; subunits
also have been identified. The  subunit is replaced by an  =
subunit
in the adult muscle.

-Bungarotoxin binds to the  and  subunits and proba=
bly blocks
both the channel and the ACh binding site. Local anesthetics and
other compounds such as phencyclidine bind to the receptor,
apparantly at the site of the sodium channel and modulate the
binding of acetylcholine to the active site. Local anesthetics also
prevent ion conductance through a direct action at the channel. The
sodium channel and the channel for the nicotinic cholinergic
receptor have some similar properties (in both structure and
sensitivity to drug action) and may have a common genetic origin.
In general terms, acetylcholine binds to the -subunits of the
receptor making the membrane more permeable to cations and causing a
local depolarization. The local depolarization spreads to an action
potential or leads to muscle contraction when summed with the action
of other receptors. Nicotinic receptors possess a relatively low
affinity for acetylcholine at rest. The affinity for acetylcholine
is increased during activation (through an allosteric mechanism
which increases the likelihood of another molecule of acetylcholine
binding to the other  subunit). At high concentrations of
acetylcholine, the affinity for acetylcholine becomes higher and the
receptor subsequently becomes desensitized. The ionophore (ion
channel) is open during the active state and local anesthetics may
bind to the open channel.
The subunit composition of nicotinic receptors differs in skeletal
muscle, autonomic ganglia and brain. The table below lists some of
the properties of receptors found in different tissues. Note that
multiple subunit compositions are possible, which may permit the
development of compounds selective for a particular combination.
Within the CNS, the 42 combination predominates.

Nicotinic antagonists
Antagonists for nicotinic receptors include such diverse compounds
as curare, -bungarotoxin and gallamine. Nicotinic receptors found
at the neuromuscular junction differ from the receptors found in
autonomic ganglia and can be distinguished both pharmacologically
and biochemically.
Gallamine (a mixed muscarinic and nicotinic antagonist) and
decamethonium are more effective antagonists at the neuromuscular
junction than at the autonomic ganglia. The spacing of the charged
nitrogens seems to be of critical importance in the selectivity of
the drugs. Gallamine and succinylcholine are used during surgery to
block nmj receptors and produce paralysis. Succinylcholine is used
more often because it can be metabolized by acetylcholinesterase to
produce inactive compounds. Note the structural similarity to
acetylcholine. Decamethonium is another nicotinic antagonist with
some selectivity for the neuromuscular junction
Ganglionic blockers include the quaternary compounds hexamethonium
and tetraethylammonium as well as the tertiary and secondary amines
mecamylamine and pempidine. While quaternary amines competitively
inhibit cholinergic responses in autonomic ganglia, tertiary and
secondary amines also have a noncompetitive component.
Ganglionic blockers are used to treat hypertension in some cases.
Because they block both sympathetic and parasympathetic responses,
their use is restricted to emergency situations or circumstances
where the patient can be monitored (orthostatic hypotension is one
of the common side effects).
Succinylcholine and decamethonium are both depolarizing blockers of
nicotinic receptors, in that they initially mimic the action of
acetylcholine. Following the initial depolarization, the
depolarizing blockers exert a long-acting blockade of the receptor,
thereby preventing further activation by acetylcholine. The
trimethylammonium group seems to be important for action as a
depolarizing blocker since compounds with a triethylammonium group
do not cause the depolarization but do block the action of
acetylcholine (see gallamine for instance).

Nicotinic agonists
Over the past several years, a variety of research groups have
focused on the development of selective nicotinic agonists.
Nicotinic agonists could be useful in the treatment of a variety of
neurological disorders including Alzheimer's disease, Parkinson's
disease and chronic pain. Epibatidine is a nicotinic agonist
isolated from the skin of an Ecuadoran frog Epipedobates tricolor
that displays potent analgesic properties.
Another nicotinic agonist, ABT-418, exhibits some cognition
enhancing properties. Note its similarity to nicotine, with an
ixoxazole moiety replacing the pyridyl group of nicotine.
Epiboxidine is a structural analogue that combines elements of both
epibatidine and ABT-418. It also is a potent nicotinic agonist.
Two other derivatives are worth noting. The azetidine analogue of
epibatidine, ABT-594, is a potent analgesic with significantly fewer
side effects than epibatidine. SIB-1508 is another nicotinic agonist
with potential utility in the treatment of Parkinson's disease.

Muscarinic receptors
Acetylcholine and carbamylcholine can bind to both muscarinic and
nicotinic receptors, yet the responses elicited by activating each
receptor differ in several ways. Muscarinic responses are slower,
may produce excitation or inhibition and involve second messenger
systems, rather than the direct opening of an ion channel.
Muscarinic receptors are G protein-coupled receptors and mediate
their responses by activating a cascade of intracellular pathways.
Muscarine is the prototypical muscarinic agonist and derives from
the fly agaric mushroom Amanita muscaria. Like acetylcholine,
muscarine contains a quaternary nitrogen important for action at the
anionic site of the receptor (an aspartate residue in transmembrane
domain III). Most muscarinic agonists obey the "rule of five" atoms
from the quateranry ammonium moiety to the terminal atom.
Muscarinic receptors are found in the parasympathetic nervous
system. Muscarinic receptors in smooth muscle regulate cardiac
contractions, gut motility and bronchial constriction. Muscarinic
receptors in exocrine glands stimulate gastric acid secretion,
salivation and lacrimation. Muscarinic receptors also are found in
the superior cervical ganglion where they can produce at least two
physiologically distinct responses. In addition, muscarinic
receptors are found throughout the brain, including the cerebral
cortex, the striatum, the hippocampus, thalamus and brainstem.
In general the classical muscarinic antagonists such as atropine
recognize a single class of binding sites as determined in binding
assays. In the 1980's, several selective muscarinic antagonists were
identified. Pirenzepine was very useful in the characterization of
M1 muscarinic receptors, while AF-DX 116 was used to identify M2
receptors in the heart. M3 receptors are found in smooth muscle and
in both exocrine glands (e.g., lacrimal glands) and endocrine glands
(e.g., pancreas). Muscarinic agonists bind heterogeneously to
receptors in both the brain and peripheral nervous system.
In the late 1980's, molecular cloning techniques identified five
different subtypes of muscarinic receptors. Each receptor shares
common features including specificity of binding for the agonists
acetylcholine and carbamylcholine and the classical antagonists
atropine and quinuclidinyl benzilate. Each receptor subtype couples
to a second messenger system through an intervening G-protein. M1,
M3 and M5 receptors stimulate phosphoinositide metabolism while M2
and M4 receptors inhibit adenylate cyclase. The tissue distribution
differs for each subtype. M1 receptors are found in the forebrain,
especially in the hippocampus and cerebral cortex. M2 receptors are
found in the heart and brainstem while M3 receptors are found in
smooth muscle, exocrine glands and the cerebral cortex. M4 receptors
are found in the neostriatum and M5 receptor mRNA is found in the
substantia nigra, usggesting that M5 receptors may regulate dopamine
release at terminals within the striatum. The structural
requirements for activation of each subtype remain to be elucidated.
Muscarinic antagonists
Muscarinic antagonists such as scopolamine and atropine are among
the oldest known molecules, originally derived from natural sources.
They are both alkaloids (natural, nitrogenous organic bases, usually
containing tertiary amines) from the nightshade plant Atropa
belladonna. The presence of an N-methyl group on atropine or
scopolamine changes the activity of the ligand, possibly by
preventing a close interaction between the ligand and the membrane
or lipophilic sites on the receptor. The methyl group also prevents
the penetration into the brain.
The potent anticholinergics are used to control the secretion of
saliva and gastric acid, slow gut motility, and prevent vomiting.
They also have a limited therapeutic use for the treatment of
Parkinson's disease. In large doses however, the muscarinic
antagonists with tertiary amines have severe central effects,
including hallucinations and memory disturbances.
In recent years, the quaternary muscarinic antagonist ipratroprium
has been used in the treatment of chronically obstructed pulmonary
disorder as an adjunct to 2 agonist therapy. M3 muscarinic
receptors mediate bronchoconstriction in the airways. Muscarinic
antagonists such as ipratropium and the long-lasting tiotropium are
effective bronchodilators.
The possible use of presynaptic antagonists to increase
acetylcholine levels has attracted some attention recently.
Muscarinic autoreceptors resemble pharmacologically the M2 receptor
found in the heart. M2 antagonists enhance acetylcholine release by
blocking the feedback inhibition produced by the action of
acetylcholine on presynaptic terminals.
Muscarinic agonists
The ability for the quaternary ammonium group to fit into an anionic
site on muscarinic receptors may be an important factor for the
binding of a ligand to muscarinic receptors. For an example of the
requirement of the quaternary amine moiety, condsider that
dimethylaminoethylacetate (the tertiary form of acetylcholine) is
1000-fold less than acetylcholine, in part due to a lower affinity
for the receptor.
The molecule of acetylcholine is flexible and may form an infinite
number of conformations from the extended to the quasi-ring
structure. The three-membered ring of acetoxycyclopropyl-
trimethylammonium iodide demonstrates the concept that the extended
form of acetylcholine contains the highest intrinsic activity. The
trans isomer has much higher activity than the cis isomer which
orients the ester and the quaternary amine together.

While the quaterany nitrogen is essential for eliciting full
muscarinic responses with muscarinic agonists, there are a few
potent muscarinic agents which contain tertiary amines (e.g.,
arecoline, oxotremorine and pilocarpine). They are potent both
peripherally and centrally although they are of limited therapeutic
value because of the wide range of cholinergic responses that they
elicit. Oxotremorine is of interest because of its ability to
produce tremors, thereby providing an early model for Parkinson's
disease.
Simple tertiary amines do not show considerable potency for the
receptor, but this can be counteracted if the rest of the molecule
binds potently to the receptor (e.g., through an ester bioisostere).
Oxotremorine fills this role with an amide group in a pyrrolidone
ring as the nitrogen replaces oxygen in a hydrogen bond acceptor
role. Arecoline (isolated originally from the betel nut) has a
reversed ester acetylcholine profile, while pilocarpine has its
ester in the cyclic form of a lactam ring, which may help increase
the binding interaction. In general, it is important to have two
sites for hydrogen bond acceptance in the ester isostere. The
orientation of the ester isostere may be important for selective
action as well.

The events associated with G protein-coupled receptor activation are
as follows.
1. Agonist binds to the receptor, which has a high affinity for
agonists at rest.
2. The binding of the agonist stabilizes a receptor
conformation promotes receptor/ G protein coupling and allows GTP to
exchange for GDP on the G protein  subunit.
3. The binding of GTP leads to the dissociation of the G
protein from the receptor, thereby lowering agonist affinity. The
agonist then dissociates from the activated receptor.
4. The G protein consists of three subunits (, , and &#6154=
3;) which
also dissociate. The  subunit activates the appropriate second
messenger system (e.g., phospholipase C for M1 receptors). The  and=

 subunits can exert independent actions.
5. The  subunit is inactivated by the hydrolysis of GTP to
form GDP by a GTPase intrinsic to the G protein (GTPase activity may
be activated by other intracellular proteins called GTPase
activating proteins [GAPs]).
6. The  subunit (with GDP bound) can then recombine with the &#6153=
8;
and  subunits. The receptor is then in a high affinity state and
ready for the binding of another agonist.

Alzheimer's disease
Alzheimer's disease is characterized by amyloid plaques and
neurofibrillary tangles. Amyloid plaques contain deposits of -
amyloid, which is a 40-42 amino acid peptide derived from amyloid
precursor protein. Neurofibrillary tangles contain a
hyperphosphorylated  protein, which forms paired helical filaments.=

Alzheimer's disease is associated with a loss of cholinergic neurons
which project from the basal forebrain to the cerebral cortex and
the hippocampus. The loss of cholinergic neurons is progressive and
results in profound memory disturbances and irreversible impairment
of cognitive function.
The cause of Alzheimer's disease is unknown, yet several genes and
gene products (proteins) have been implicated.
• Mutations in APP (a small percentage of all Alzheimer's
patients
• Presenillin mutations (may promote the formation of -
amyloid)
• Apolipoprotein E allele (E4 is associated with an increased
risk of Alzheimer's disease)

Drug development
Recent efforts have focused on the development of centrally active
muscarinic receptor agonists for the treatment of Alzheimer's
disease. The rationale for therapy involves replacement of
acetylcholine, which is depleted in Alzheimer's patients as the
basal forebrain neurons degenerate. An ideal candidate for a drug
would have several features including high CNS penetrance, high
efficacy and selectivity for forebrain receptors and a low incidence
of side effects.
The muscarinic agonist xanomeline is an arecoline derivative with
very high affinity and selectivity for M1 muscarinic receptors. It
contains a 1,2,5-thiadiazole ring, which is more stable than the
ester found in arecoline. In CDD-0102 a 1,2,4-oxadiazole moiety
serves as a suitable ester isostere.
Reference:
http://www.neurosci.pharm.utoledo.edu/MBC3320/acetylcholine.htm


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