Acetylcholine receptor sites

Figure 4.14 Gated ion channel (ligand activated, acetylcholine) at neuromuscular junction, (a) receptor sites unoccupied and gate closed (b) acetylcholine receptor sites occupied and gate is open allowing influx of ion...

Mecamylamine is a noncompetitive antagonist at the nicotinic acetylcholine receptor site. If mecamylamine could effectively block the physiological and reinforcing effects of cigarette smoking, this should, in theory, lead to eventual extinction of the behavior. When mecamylamine is administered to smokers, it has increased rather than decreased ad libitum smoking behavior, presumably due to smokers... 

Curare-like muscle relaxants act by blocking acetylcholine receptor sites, thus eliminating transmission of nerve impulses at the neuromuscular junction. There are two acetylcholine-like groupings in the molecules, and the drugs, therefore, probably span and block several receptor sites. The neurotransmitter acetylcholine is also a quaternary ammonium compound. The natural material present in curare is tubocurarine, a complex alkaloid that is a mono-quaternary salt. Under physiological conditions, the tertiary amine will be almost completely protonated (see Section 4.9), and the compound will similarly possess two positively charged centres. 

Certain plants of the family Solanaceae, such as Atropa belladonna L., Hyoscyamus niger L., and Datura stramonium L., have been used medicinally for centuries in Europe because they contain tropane-type alkaloids.For example, atropine (1) [a racemic mixture of (+)- and (—)-hyoscyamine (2)] and (-)-hyoscyamine are competitive antagonists at the muscarinic acetylcholine receptor site, leading to antispasmodic and antiallergic effects. Scopolamine [(—)-hyoscine)] (3) is used in a transdermal patch for the prevention of motion sickness. Since these tropane alkaloids penetrate the blood-brain barrier, they also have psychoactive effects. ... 

Quaternary Ammonium Catechols in Acetylcholine Receptor Site-Directed Reactions... 

Nicotine and the neurotransmitter acetylcholine, which acts on maintenance neurons, have similar structures, as Figure 14.28 illustrates. Nicotine molecules are therefore able to bind to acetylcholine receptor sites and trigger many of acetylcholines effects, including relaxation and increased digestion, which... 

Suxamethonium consists of two acetylcholine molecules linked together. Initially, it acts like acetylcholine by depolarizing the motor end-plate. However, unlike acetylcholine, which on dissociation from the receptor is immediately destroyed by acetylcholinesterase present in the neuromuscular junction, suxamethonium is hydrolysed by a (pseudo)cholinesterase present in the plasma but not at the neuromuscular junction. Most of an injected dose of suxamethonium is normally destroyed before it reaches the neuromuscular junction. If the activity of plasma cholinesterase in a particular patient is reduced, more of the suxamethonium reaches the neuromuscular junction and its action is proportionately prolonged. The molecules of suxamethonium that reach the acetylcholine receptor sites interact repeatedly with them, producing prolonged depolarization of the motor end-plate, which becomes surrounded by an electrically inactive zone. The end-result is flaccid paralysis. The action of suxamethonium is terminated by diffusion away from the neuromuscular junction. Hydrolysis results in choline and succinylmonocholine, which has a very weak competitive blocking action and is further slowly hydrolysed by plasma cholinesterase to choline and succinic acid. 

Atropine antagonizes OP poisoning by blocking acetylcholine receptor sites... 

Compounds having structural similarity with acetylcholine (1) such as bephenium (3) or thenium (4) are reported to exert their action on helminths by competing for the acetylcholine receptor site. The difference between these compounds and acetylcholine is that the former are not biodegraded by AChE and, therefore, the depolarisation effect persists very long. The net results is the contraction of the muscle causing spastic paralysis of the worm. 

The compounds of this class may not bear any obvious similarity with the acetylcholine molecule but would exert the anthelmintic action by blocking the acetylcholine receptor site. Consequently, acetylcholine is unable to increase the permeability of the membrane to initiate a depolarisation effect. 

Cartap is also an important insecticide acting at the nicotinic acetylcholine receptor site. It causes insects to stop feeding, is systemic, and has a low mammalian toxicity. It should therefore be a perfect insecticide. Cartap is not toxic per se, but is biologically converted to the cholinergic agonist nereistoxin, described later. 

Although atropine is a known antidote against several toxic substances, its overdose can cause severe poisoning. As with other tropane alkaloids, atropine competitively blocks muscarinic acetylcholine receptor sites. This results in dilation of the pupil of the eye (mydriatic effect), dryness of the mucous membranes, especially of the mouth, and inhibition of activity of sweat glands (parasympatholytic action). At toxic doses, it causes palpitation, speech disturbance. 

When d-tubocurarine binds at the acetylcholine receptor site membrane. This prevents a nerve impulse, and results in paralysis. 

Michalek, H., Fortuna, S., Volpe, M.T., et al., 1990. Age-related differences in the recovery rate of brain cholinesterases, choline acetyltransferase and muscarinic acetylcholine receptor sites after a subacute intoxication of rats with the anticholinesterase agent, isofluorophate. Acta Neurobiol. Exp. (Wars)... 

Coupling between the nicotinic acetylcholine receptor site and the ionic channel site. Ann. N. Y. Acad. Sci. 358, 239—252 (1980). 

SoBEL, A., T. Heidmann, J. Hofler, and J.-P. Changeux Distinct protein components from Torpedo marmorata membranes carry the acetylcholine receptor site and the binding site for local anesthetics and histrionicotoxin. Proc. Nat. Acad. Sci. (USA) 75, 510—514 (1978). 

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