Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Allosteric Regulation / drug effects
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Animals
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Brain / drug effects
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Brain / metabolism*
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CHO Cells
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Cricetinae
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Cricetulus
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Drug Discovery*
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Drug Evaluation, Preclinical
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Humans
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Imidazoles / chemistry*
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Imidazoles / metabolism
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Imidazoles / pharmacokinetics
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Imidazoles / pharmacology*
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Indoles / chemistry*
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Indoles / metabolism
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Indoles / pharmacokinetics
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Indoles / pharmacology*
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Male
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Rats
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Receptor, Muscarinic M5 / chemistry
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Receptor, Muscarinic M5 / metabolism*
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Structure-Activity Relationship
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Substrate Specificity
Substances
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9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo(2,1-a)isoindol-5(9bH)-one
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Imidazoles
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Indoles
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Receptor, Muscarinic M5