Handbook of psychopharmacology

Actions of acetylcholine in the periphery are the result of activation of either the ionotropic nicotinic receptor or the metabotropic muscarinic receptor. In the mammalian central nervous system (CNS)c, both nicotinic and muscarinic receptor subtypes are present on neurons, although there is as yet

https://pharmrev.aspetjournals.org/content/pharmrev/50/2/279.full.pdf

International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors

Complementary DNAs for three different muscarinic acetylcholine receptors were isolated from a rat cerebral cortex library, and the cloned receptors were expressed in mammalian cells. Analysis of human and rat genomic clones indicates that there are at least four functional muscarinic receptor genes and that these genes lack introns in the coding sequence. This gene family provides a new basis for evaluating the diversity of muscarinic mechanisms in the nervous system.

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Identification of a family of muscarinic acetylcholine receptor genes

In 1914, Sir Henry Dale provided the basis for the classical and comfortable definition of muscarinic and nicotinic acetylcholine receptors: Muscarinic receptors are selectively activated by muscarine and blocked by atropine; nicotinic receptors are activated by nicotine and blocked by curare. This definition lasted over 60 years, despite isolated reports that the picture might not be so simple. We now know, as the result of molecular biological studies, that there are multiple variants of both muscarinic and nicotinic receptors . These receptors are members of two quite separate gene superfamilies and only share the property of being activated by the same ligand, acetylcholine. The aim of this review is to discuss the structure, function, and binding properties of the different muscarinic receptor species, attempting where possible to coordinate the diverse experimental data into a uniform picture. For a more comprehensive review on muscarinic receptors, readers are di­ rected to a recent book by Brown (l).

Muscarinic Receptor Subtypes

Muscarinic receptors--characterization, coupling and function.

Some antagonists exhibit tissue selectivity in their pharmacological antagonism of muscarinic responses. However, the affinity constants for equilibrium binding of classical antagonists to muscarinic receptors in subcellular preparations have shown only small variations in different peripheral tissues and regions of the brain. The binding curves do not deviate significantly from the simple Langmuir isotherm, indicating apparent homogeneity of the receptor population in any given region. In contrast, heterogeneity has been detected by agonist binding studies but this may arise from different environmental or coupling restraints on the agonist-induced conformational change and cannot be taken as evidence for different receptor subtypes. We report here binding studies using a new anti-muscarinic drug, pirenzepine, in which we found heterogeneity of binding that correlates well with the pharmacological activity.

Pirenzepine distinguishes between different subclasses of muscarinic receptors

Pirenzepine has been shown to evoke a variety of antimuscarinic effects in animals. However, in contrast to classical antimuscarinic drugs, pirenzepine inhibits gastric acid secretion at much lower doses than those required to block smooth muscle action and to cause tachycardia. To investigate this novel behaviour we have compared the binding properties of pirenzepine to muscarinic receptors with those of a classical muscarinic antagonist, N-methyl-scopolamine. Binding has been determined in subcellular preparations of the sublingual, submandibular, parotid and lacrimal glands, smooth muscle of ileum and stomach, heart and several brain regions of the rat. Whereas N-methyl-scopolamine binds to an apparently uniform population of muscarinic receptors with little regional variation in affinity constant, the binding of pirenzepine in peripheral tissues is characterised by its low affinity in smooth muscle and the heart and considerably higher affinities to muscarinic receptors in exocrine glands and fundus mucosa, in agreement with the pharmacological profile of the drug. Furthermore, within the central nervous system and some exocrine glands, pirenzepine distinguishes between subclasses of muscarinic receptors which are not detected by classical antagonists. This evidence suggests that the unusual receptor binding properties of pirenzepine may make its selective antimuscarinic action possible.

Pirenzepine--a ligand with original binding properties to muscarinic receptors.

Muscarinic receptor subclasses: evidence from binding studies.

An examination of the binding of antagonists to the receptors in rat cerebral cortex has shown that this occurs to an apparently uniform set of sites (8). Furthermore, the binding constants so obtained are in close agreement with those estimated by antagonism of the contraction of the longitudinal smooth muscle of guinea pig ileum. However, it has been reported by Barlow et al. (1) that the activity of some antagonists on guinea pig heart was not identical to that on the ileum.

Hammer R

Papers

Pirenzepine distinguishes between different subclasses of muscarinic receptors

Pirenzepine--a ligand with original binding properties to muscarinic receptors.

Muscarinic receptor subclasses: evidence from binding studies.

“Binding States” of Muscarinic Receptors