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

Haibo Yu; Meng Wu; Steven D Townsend; Beiyan Zou; Shunyou Long; J Scott Daniels; Owen B McManus; Min Li; Craig W Lindsley; Corey R Hopkins

doi:10.1021/cn200065b

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

ACS Chem Neurosci. 2011 Oct 19;2(10):572-577. doi: 10.1021/cn200065b.

Authors

Haibo Yu¹, Meng Wu, Steven D Townsend, Beiyan Zou, Shunyou Long, J Scott Daniels, Owen B McManus, Min Li, Craig W Lindsley, Corey R Hopkins

Affiliation

¹ Department of Neuroscience, High Throughput Biology Center, Johns Hopkins University, Baltimore, Maryland 21205, United States.

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.

Abstract

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