Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders

Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt Medical Center, Nashville, TN 37232, USA.
Trends in Pharmacological Sciences (Impact Factor: 11.54). 03/2009; 30(3):148-55. DOI: 10.1016/
Source: PubMed


Muscarinic acetylcholine receptors (mAChRs) have long been viewed as viable targets for novel therapeutic agents for the treatment of Alzheimer's disease (AD) and other disorders involving impaired cognitive function. More recent evidence indicates that mAChR activators might also have utility in treating psychosis and other symptoms associated with schizophrenia and other central nervous system (CNS) disorders. Efforts to develop mAChR subtype-selective agonists have been hampered by difficulty in achieving high selectivity for individual mAChR subtypes important for CNS function (M(1) and M(4)) and adverse effects due to activation of peripheral mAChRs (especially M(2) and M(3)). Major advances have now been achieved in the discovery of allosteric agonists and positive allosteric modulators of M(1) and M(4) that show greater selectivity for individual mAChR subtypes than do previous mAChR agonists. Early studies indicate that these allosteric mAChR activators have properties needed for optimization as potential clinical candidates and have robust effects in animal models that predict efficacy in the treatment of AD, schizophrenia and related disorders.

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    • "In contrast, allosteric sites are less evolutionarily conserved across receptor subtypes and have afforded exciting opportunities to achieve true subtype selectivity, as well as diverse pharmacology by stabilizing unique, activated conformations of the receptors. Moreover, allosteric sites are generally lipophilic pockets, which could targeted by unique small-molecule chemotypes that are structurally distinct from endogenous ligands (Conn et al., 2009b; Wenthur et al., 2014). With this in mind, the MLP undertook screening efforts to identify selective positive allosteric modulators (PAMs) of mAChRs that could be used to dissect the individual contributions of these receptors to the therapeutic efficacy of pan-mAChR agonists. "
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