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

Gentry PR, Kokubo M, Bridges TM, Cho HP, Smith E, Chase P, Hodder PS, Utley TJ, Rajapakse A, Byers F, Niswender CM, Morrison RD, Daniels JS, Wood MR, Conn PJ, Lindsley CW
ChemMedChem. 2014 9 (8): 1677-82

PMID: 24692176 · PMCID: PMC4116439 · DOI:10.1002/cmdc.201402051

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.

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

MeSH Terms (11)

Acetophenones Animals Drug Evaluation, Preclinical Half-Life Humans Isoxazoles Molecular Probes Muscarinic Antagonists Protein Binding Rats Receptor, Muscarinic M5

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