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Discovery, Synthesis, and Structure Activity Relationship of a Series of N-Aryl- bicyclo[2.2.1]heptane-2-carboxamides: Characterization of ML213 as a Novel KCNQ2 and KCNQ4 Potassium Channel Opener.

ABSTRACT: Herein we report the discovery, synthesis and evaluation of a series of N-Aryl-bicyclo[2.2.1]heptane-2-carboxamides as selective KCNQ2 (K(v)7.2) and KCNQ4 (K(v)7.4) channel openers. The best compound, 1 (ML213) has an EC(50) of 230 nM (KCNQ2) and 510 nM (KCNQ4) and is selective for KCNQ2 and KCNQ4 channels versus a large battery of related potassium channels, as well as affording modest brain levels. This represents the first report of unique selectivity profile for KCNQ2 and KCNQ4 over the other channels (KCNQ1/3/5) and as such should prove to be a valuable tool compound for understanding these channels in regulating neuronal activity.

SUBMITTER: Yu H

PROVIDER: S-EPMC3223964 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Discovery, Synthesis, and Structure Activity Relationship of a Series of N-Aryl- bicyclo[2.2.1]heptane-2-carboxamides: Characterization of ML213 as a Novel KCNQ2 and KCNQ4 Potassium Channel Opener.

Yu Haibo H Wu Meng M Townsend Steven D SD Zou Beiyan B Long Shunyou S Daniels J Scott JS McManus Owen B OB Li Min M Lindsley Craig W CW Hopkins Corey R CR

ACS chemical neuroscience 20111001 10

Herein we report the discovery, synthesis and evaluation of a series of N-Aryl-bicyclo[2.2.1]heptane-2-carboxamides as selective KCNQ2 (K(v)7.2) and KCNQ4 (K(v)7.4) channel openers. The best compound, 1 (ML213) has an EC(50) of 230 nM (KCNQ2) and 510 nM (KCNQ4) and is selective for KCNQ2 and KCNQ4 channels versus a large battery of related potassium channels, as well as affording modest brain levels. This represents the first report of unique selectivity profile for KCNQ2 and KCNQ4 over the othe ...[more]

PMID: 22125664

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