Mecamylamine
Encyclopedia
Mecamylamine is a nonselective
and noncompetitive antagonist
of the nicotinic acetylcholine receptor
s that was introduced in the 1950s as an antihypertensive
agent.
in treating hypertension
, but, like most ganglionic blockers, it is more often used now as a research tool.
Mecamylamine is also sometimes used as an anti-addictive drug to help people stop smoking tobacco, and is now more widely used for this application than it is for lowering blood pressure. This effect is thought to be due to its blocking α3β4
nicotinic receptors in the brain.
In a recent double-blind, placebo-controlled Phase II trial in Indian patients with major depression, (S)-mecamylamine (TC-5214) appeared to have efficacy as an augmentation
therapy. This is the first substantive evidence that shows that compounds where the primary pharmacology is antagonism to neuronal nicotinic receptors will have antidepressant properties. TC-5214 is currently in Phase III of clinical development as an add-on treatment and on stage II as a monotherapy treatment for major depression. The first results reported from the Phase III trials showed that TC-5214 failed to meet the primary goal and the trial did not replicate the effects that had been encouraging in the Phase II trial. Development is funded by Targacept and AstraZeneca. It did not produce meaningful, beneficial results on patients as measured by changes on the Montgomery-Asberg Depression Rating Scale after eight weeks of treatment as compared with placebo.
(S)-(+)-Mecamylamine dissociates
more slowly from alpha-4 beta-2 and alpha-3 beta-4 receptors than does the (R)-(-)-enantiomer
. The pKa value is 11.2.
A small SAR study was undertaken by Suchocki et al.
, which is reacted under Ritter reaction
conditions
with hydrogen cyanide in concentrated sulfuric acid
, giving N-(2,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)formamide, the reduction of which by lithium aluminum hydride leads to mecamylamine.
Binding selectivity
Binding selectivity refers to the differing affinities with which different ligands bind to a substrate forming a complex. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate...
and noncompetitive antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
of the nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
s that was introduced in the 1950s as an antihypertensive
Antihypertensive
The antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from...
agent.
Uses
Mecamylamine has been used as a ganglionic blockerGanglionic blocker
A ganglionic blocker is a type of medication that inhibits postganglionic transmission, primarily by acting as a nicotinic antagonist....
in treating hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, but, like most ganglionic blockers, it is more often used now as a research tool.
Mecamylamine is also sometimes used as an anti-addictive drug to help people stop smoking tobacco, and is now more widely used for this application than it is for lowering blood pressure. This effect is thought to be due to its blocking α3β4
Alpha-3 beta-4 nicotinic receptor
The alpha-3 beta-4 nicotinic receptor, also known as the α3β4 receptor, is a type of nicotinic acetylcholine receptor, consisting of α3 and β4 subunits. It is located in the brain, where activation yields post- and presynaptic excitation....
nicotinic receptors in the brain.
In a recent double-blind, placebo-controlled Phase II trial in Indian patients with major depression, (S)-mecamylamine (TC-5214) appeared to have efficacy as an augmentation
Augmentation (psychiatry)
Augmentation is the combination of two or more drugs to achieve better treatment results....
therapy. This is the first substantive evidence that shows that compounds where the primary pharmacology is antagonism to neuronal nicotinic receptors will have antidepressant properties. TC-5214 is currently in Phase III of clinical development as an add-on treatment and on stage II as a monotherapy treatment for major depression. The first results reported from the Phase III trials showed that TC-5214 failed to meet the primary goal and the trial did not replicate the effects that had been encouraging in the Phase II trial. Development is funded by Targacept and AstraZeneca. It did not produce meaningful, beneficial results on patients as measured by changes on the Montgomery-Asberg Depression Rating Scale after eight weeks of treatment as compared with placebo.
(S)-(+)-Mecamylamine dissociates
Dissociation constant
In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into...
more slowly from alpha-4 beta-2 and alpha-3 beta-4 receptors than does the (R)-(-)-enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
. The pKa value is 11.2.
A small SAR study was undertaken by Suchocki et al.
Chemistry
Mecamylamine is synthesized from campheneCamphene
Camphene is bicyclic monoterpene. It is nearly insoluble in water, but very soluble in common organic solvents. It volatilizes readily at room temperature and has a pungent smell. It is a minor constituent of many essential oils such as turpentine, cypress oil, camphor oil, citronella oil,...
, which is reacted under Ritter reaction
Ritter reaction
The Ritter reaction is a chemical reaction that transforms a nitrile into a N-alkyl amide using various alkylating reagents, for example, strong acid and isobutylene....
conditions
with hydrogen cyanide in concentrated sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...
, giving N-(2,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)formamide, the reduction of which by lithium aluminum hydride leads to mecamylamine.