Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe

Research output: Contribution to journalJournal articleResearchpeer-review

  • Gentry, Patrick Ryan
  • Masaya Kokubo
  • Thomas M Bridges
  • Hyekyung P Cho
  • Emery Smith
  • Peter Chase
  • Peter S Hodder
  • Thomas J Utley
  • Anuruddha Rajapakse
  • Frank Byers
  • Colleen M Niswender
  • Ryan D Morrison
  • J Scott Daniels
  • Michael R Wood
  • P Jeffrey Conn
  • Craig W Lindsley

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.

Original languageEnglish
Issue number8
Pages (from-to)1677-82
Number of pages6
Publication statusPublished - Aug 2014
Externally publishedYes

Bibliographical note

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

    Research areas

  • Acetophenones/chemistry, Animals, Drug Evaluation, Preclinical, Half-Life, Humans, Isoxazoles/chemistry, Molecular Probes/chemistry, Muscarinic Antagonists/chemistry, Protein Binding, Rats, Receptor, Muscarinic M5/antagonists & inhibitors

ID: 213599660