Five subtypes of muscarinic receptors have been identified, primarily on the basis of data from ligand-binding and cDNA-cloning experiments (see Chapters 6 and 7). A standard terminology (M1 through M5) for these subtypes is now in common use, and evidence—based mostly on selective agonists and antagonists— indicates that functional differences exist between several of these subtypes. The X-ray crystallographic structures of the M1–4 subtypes of muscarinic receptors have been reported. The structures of the M1–4 receptors are very similar in the inactive state with inverse agonist or antagonist bound to the receptor. The binding pocket for orthosteric ligands lies well within the plane of the plasma membrane, and the amino acids composing the site are conserved among muscarinic receptor subtypes. This observation underscores the difficulty in identifying subtype-selective ligands. A structure forming a “lid” separates the orthosteric binding site from an upper cavity termed the “vestibule” (Figure 8–1). The binding site for allosteric ligands is the extracellular vestibule. Among the receptor subtypes, the extracellular vestibule is comprised of different amino acids that provide distinctive sites for binding by selective allosteric modulators. The M1 receptor subtype is located on central nervous system (CNS) neurons, autonomic postganglionic cell bodies, and many presynaptic sites. M2 receptors are located in the myocardium, smooth muscle organs, and some neuronal sites. M3 receptors are most common on effector cell membranes, especially glandular and smooth muscle cells. M4 and M5 receptors are less prominent and appear to play a greater role in the CNS than in the periphery.
Muscarinic antagonists are sometimes called parasympatholytic because they block the effects of parasympathetic autonomic discharge. However, the term “antimuscarinic” is preferable.
Naturally occurring compounds with antimuscarinic effects have been known and used for millennia as medicines, poisons, and cosmetics. Atropine is the prototype of these drugs. Many similar
FIGURE 8–1 Upper portion of the M3 receptor with a “lid” formed by tyrosine (Tyr) residues separating the cavity into an upper portion called the vestibule from the lower portion, with the orthosteric binding site depicted as occupied by tiotropium. The receptor is in black, tiotropium is in yellow, and the receptor surface is in green. (Adapted, with permission, from Kruse AC et al: Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature 2012;482:552. Copyright © 2012 Macmillan Publishers Ltd.) plant alkaloids are known, and hundreds of synthetic antimuscarinic compounds have been prepared.
A. Source and Chemistry
Atropine and its naturally occurring congeners are tertiary amine alkaloid esters of tropic acid (Figure 8–2). Atropine (hyoscyamine) is found in the plant Atropa belladonna, or deadly nightshade, and in Datura stramonium, also known as jimson-weed (Jamestown weed), sacred Datura, or thorn apple. Scopolamine (hyoscine) occurs in Hyoscyamus niger, or henbane, as the l(−) stereoisomer.
FIGURE 8–2 The structure of atropine (oxygen [red] at [1] is missing) or scopolamine (oxygen present). In homatropine, the hydroxymethyl at [2] is replaced by a hydroxyl group, and the oxygen at [1] is absent.
Naturally occurring atropine is l(−)-hyoscyamine, but the compound readily racemizes, so the commercial material is racemic d,l-hyoscyamine. The l(−) isomers of both alkaloids are at least 100 times more potent than the d(+) isomers.