Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins.
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ABSTRACT:
SUBMITTER: Bridges TM
PROVIDER: S-EPMC3875304 | biostudies-literature | 2009 Jun
REPOSITORIES: biostudies-literature
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Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins.
Bridges Thomas M TM Marlo Joy E JE Niswender Colleen M CM Jones Carrie K CK Jadhav Satyawan B SB Gentry Patrick R PR Plumley Hyekyung C HC Weaver C David CD Conn P Jeffrey PJ Lindsley Craig W CW
Journal of medicinal chemistry 20090601 11
This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca(2+) mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity vers ...[more]
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