Discovery, Synthesis and Characterization of a Highly Muscarinic Acetylcholine Receptor (mAChR)‐Selective M5‐Orthosteric Antagonist, VU0488130 (ML381): A Novel Molecular Probe. Issue 8 (1st April 2014)

• Record Type: Journal Article
• Authors: Gentry, Patrick R.; Kokubo, Masaya; Bridges, Thomas M.; Cho, Hyekyung P.; Smith, Emery; Chase, Peter; Hodder, Peter S.; Utley, Thomas J.; Rajapakse, Anuruddha; Byers, Frank; Niswender, Colleen M.; Morrison, Ryan D.; Daniels, J. Scott; Wood, Michael R.; Conn, P. Jeffrey; Lindsley, Craig W.
• Is Part Of: ChemMedChem. Volume 9:Issue 8(2014:Aug.)
• Page Start: 1677
• Page End: 1682
• Publication Date: 2014-04-01
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201402051
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 n<sc>M</sc>, hM₅<italic>K</italic>_i=340 n<sc>M</sc>, M₁–M₄ IC₅₀ &gt;30 μ<sc>M</sc>), 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.</p> </abstract>