title: Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe.
abstract: Of the five G-protein-coupled muscarinic acetylcholine receptors (mAChRs; M1-M5), M5 is the least explored and understood due to a lack of mAChR subtype-selective ligands. We recently performed a high-throughput functional screen and identified a number of weak antagonist hits that are selective for the M5 receptor. Here, we report an iterative parallel synthesis and detailed molecular pharmacologic profiling effort that led to the discovery of the first highly selective, central nervous system (CNS)-penetrant M5-orthosteric antagonist, with sub-micromolar potency (hM5 IC50=450 nM, hM5 Ki=340 nM, M1-M4 IC50>30 μM), enantiospecific inhibition, and an acceptable drug metabolism and pharmacokinetics (DMPK) profile for in vitro and electrophysiology studies. This compound will be a powerful tool and molecular probe for the further investigation into the role of M5 in addiction and other diseases.
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center (MLPCN), Vanderbilt University Medical Center, Nashville, TN 37232-6600 (USA).
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Gentry
authors.forename: Masaya
authors.initials: M
authors.lastname: Kokubo
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Emery
authors.initials: E
authors.lastname: Smith
authors.forename: Peter
authors.initials: P
authors.lastname: Chase
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hodder
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Utley
authors.forename: Anuruddha
authors.initials: A
authors.lastname: Rajapakse
authors.forename: Frank
authors.initials: F
authors.lastname: Byers
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morrison
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000098:Acetophenones / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D015335:Molecular Probes / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D018727:Muscarinic Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D043642:Receptor, Muscarinic M5 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C000596167:5-((3-acetylphenoxy)methyl)-N-methyl-N-(1-(pyridin-2-yl)ethyl)isoxazole-3-carboxamide; D000098:Acetophenones; D007555:Isoxazoles; D015335:Molecular Probes; D018727:Muscarinic Antagonists; D043642:Receptor, Muscarinic M5
keywords: acetylcholine; antagonists; molecular probes; muscarinic acetylcholine receptors; orthosteric ligands