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J Med Chem. 2012 Aug 9;55(15):6975-9. doi: 10.1021/jm300700v. Epub 2012 Jul 26.

Discovery of a series of 2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)acetamides as novel molecular switches that modulate modes of K(v)7.2 (KCNQ2) channel pharmacology: identification of (S)-2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)butanamide (ML252) as a potent, brain penetrant K(v)7.2 channel inhibitor.

Author information

1
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.

Abstract

A potent and selective inhibitor of KCNQ2, (S)-5 (ML252, IC(50) = 69 nM), was discovered after a high-throughput screen of the MLPCN library was performed. SAR studies revealed a small structural change (ethyl group to hydrogen) caused a functional shift from antagonist to agonist activity (37, EC(50) = 170 nM), suggesting an interaction at a critical site for controlling gating of KCNQ2 channels.

PMID:
22793372
PMCID:
PMC3530927
DOI:
10.1021/jm300700v
[Indexed for MEDLINE]
Free PMC Article

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