Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders.
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.
Conn
P Jeffrey
PJ
Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt Medical Center, Nashville, TN 37232, USA. jeff.conn@vanderbilt.edu
Jones
Carrie K
CK
Lindsley
Craig W
CW
D000494:Allosteric Regulation; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002491:Central Nervous System Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy* / Q000378:metabolism; D018721:Muscarinic Agonists / Q000494:pharmacology / Q000627:therapeutic use; D018727:Muscarinic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D043643:Receptor, Muscarinic M1 / Q000502:physiology; D043588:Receptor, Muscarinic M4 / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism
D014150:Antipsychotic Agents; D002491:Central Nervous System Agents; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic