Derivatives of ACh Methacholine Carbachol and Bethanechol

The therapeutic usefulness of ACh is limited by (1) its lack of selectivity as an agonist for different types of choli-noreceptors and (2) its rapid degradation by cholin-esterases. These limitations have been circumvented in part by the development of three choline ester derivatives of ACh: methacholine (Provocholine), carbachol (Isopto Carbachol, Miostat) and bethanechol (Urecholine). Methacholine differs from ACh only in the addition of a methyl group at the p-carbon of ACh. This modification greatly increases its selectivity for muscarinic receptors relative to nicotinic receptors, and it renders methacholine resistant to the pseudo-ChE in the plasma and decreases its susceptibility to AChE, thereby increasing its potency and duration of action compared to those of ACh. Carbachol differs from ACh only in the substitution of a carbamoyl group for the terminal methyl group of ACh. This substitution makes carbachol completely resistant to degradation by cholinesterases but does not improve its selectivity for muscarinic versus nicotinic receptors. Bethanechol combines the addition of the methyl group and the substitution of the terminal carbamoyl group, producing a drug that is a selective agonist of muscarinic receptors and is resistant to degradation by cholinesterases.

All of these drugs are very hydrophilic and membrane impermeant because they retain the quaternary ammonium group of the choline moiety of ACh.

Pilocarpine is a naturally occurring cholinomimetic alkaloid that is structurally distinct from the choline esters. It is a tertiary amine that crosses membranes relatively easily. Therefore, it is rapidly absorbed by the cornea of the eye, and it can cross the blood-brain barrier. Pilocarpine is a pure muscarinic receptor agonist, and it is unaffected by cholinesterases. Muscarine is an alkaloid with no therapeutic use, but it can produce dangerous cholinomimetic stimulation following ingestion of some types of mushrooms (e.g., Inocybes).

minated only by its hydrolysis. There is no reuptake system in cholinergic nerve terminals to reduce the concentration of ACh in a synaptic cleft, unlike the reup-take systems for other neurotransmitters such as dopamine, serotonin, and norepinephrine. Therefore, inhibition of AChE can greatly prolong the activation of cholinoreceptors by ACh released at a synapse.

Pseudo-ChE (also known as butyryl-, plasma, and nonspecific cholinesterase) has a widespread distribution, with enzyme especially abundant in the liver, where it is synthesized, and in the plasma. In spite of the abundance of pseudo-ChE, its physiological function has not been definitively identified. It does, however, play an important role in the metabolism of such clinically important compounds as succinylcholine, pro-caine, and numerous other esters.

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