Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375).

Gentry PR, Kokubo M, Bridges TM, Kett NR, Harp JM, Cho HP, Smith E, Chase P, Hodder PS, Niswender CM, Daniels JS, Conn PJ, Wood MR, Lindsley CW
J Med Chem. 2013 56 (22): 9351-5

PMID: 24164599 · PMCID: PMC3876027 · DOI:10.1021/jm4013246

A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for the M5 subtype. ML375 is a highly selective M5 NAM with submicromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1-M4 IC50 > 30 μM), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition.

MeSH Terms (16)

Allosteric Regulation Animals Brain CHO Cells Cricetinae Cricetulus Drug Discovery Drug Evaluation, Preclinical Humans Imidazoles Indoles Male Rats Receptor, Muscarinic M5 Structure-Activity Relationship Substrate Specificity

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