Commentary Allosteric Antagonists of the Muscarinic Acetylcholine Receptor

Muscarinic acetylcholine receptors belong to a superfamily of structurally related proteins which possess seven transmembrane spanning regions and couple to G-proteins [1-4]. Thus far, five distinct muscarinic receptor subtypes (designated ml-m5) are known to exist based on recent molecular cloning studies [2, 5, 6]. Earlier knowledge of muscarinic receptor heterogeneity was based on binding and functional studies using several subtype selective antagonists (e.g. pirenzepine, AF-DX 116, 4-DAMP and haxahydrosiladifenidol) [see Ref. 7 for review]. For the most part, the interaction of these selective antagonists with muscarinic receptors has been interpreted in the context of a simple competitive bimolecular reaction which obeys the law of mass action. In fact, the use of selective antagonists as a pharmacological tool to identify receptor types and subtypes is based on this premise [8]. However, the complex binding behavior exhibited by other compounds has pointed to the existence of an allosteric (secondary) binding site on the muscarinic receptor.