Five subtypes of muscarinic acetylcholine receptors (mAChRs) are expressed throughout the body, where they exert diverse effects, such as smooth muscle contraction, glandular secretion, thermoregulation, and regulation of behavior, learning, and cognition. MAChRs have been implicated in schizophrenia and Alzheimer’s disease (AD), making them attractive as candidate drug targets. Several cholinergic agonists have shown promise for treating these conditions, but most of these drugs bind to the acetylcholine binding site—which is highly conserved across receptor subtypes—and therefore have undesirable side effects. Because of this, drug developers have recently turned to allosteric agonists, which activate receptors by binding to subtype-specific domains outside the acetylcholine binding site. Jones et al. Report that one such agonist, which is highly specific for M1 mAChRs, produced effects in mice similar to effects of atypical antipsychotic drugs, without producing undesirable side effects. Moreover, the drug regulated processing of amyloid precursor protein, suggesting that it may effectively treat AD.
Subtype Specificity of an Allosteric mAChR Agonist
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