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

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  • 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.

OriginalsprogEngelsk
TidsskriftChemMedChem
Vol/bind9
Udgave nummer8
Sider (fra-til)1677-82
Antal sider6
ISSN1860-7179
DOI
StatusUdgivet - aug. 2014
Eksternt udgivetJa

ID: 213599660