title: Classics in Chemical Neuroscience: Xanomeline.
abstract: Xanomeline (1) is an orthosteric muscarinic acetylcholine receptor (mAChR) agonist, often referred to as M1/M4-preferring, that received widespread attention for its clinical efficacy in schizophrenia and Alzheimer's disease (AD) patients. Despite the compound's promising initial clinical results, dose-limiting side effects limited further clinical development. While xanomeline, and related orthosteric muscarinic agonists, have yet to receive approval from the FDA for the treatment of these CNS disorders, interest in the compound's unique M1/M4-preferring mechanism of action is ongoing in the field of chemical neuroscience. Specifically, the promising cognitive and behavioral effects of xanomeline in both schizophrenia and AD have spurred a renewed interest in the development of safer muscarinic ligands with improved subtype selectivity for either M1or M4. This Review will address xanomeline's overall importance in the field of neuroscience, with a specific focus on its chemical structure and synthesis, pharmacology, drug metabolism and pharmacokinetics (DMPK), and adverse effects.
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Bender
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.|Department of Pharmacology, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.|Department of Pharmacology, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.|Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Craig W
authors.identifier: 0000-0003-0168-1445
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000818:Animals; D002493:Central Nervous System Diseases / Q000188:drug therapy*; D006801:Humans; D018721:Muscarinic Agonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D009488:Neurosciences; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018721:Muscarinic Agonists; D011725:Pyridines; D013830:Thiadiazoles; C075257:xanomeline
keywords: Alzheimer’s disease; Xanomeline; allosteric modulation; antipsychotic; muscarinic acetylcholine receptors; schizophrenia