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

Research output: Contribution to journalArticle

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 v7.2) and KCNQ4 (K v7.4) 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 profiles 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.

Original languageEnglish (US)
Pages (from-to)572-577
Number of pages6
JournalACS Chemical Neuroscience
Volume2
Issue number10
DOIs
StatePublished - Oct 19 2011

Keywords

  • KCNQ2
  • KCNQ4
  • Kv7
  • ML218
  • MLPCN probe
  • activator
  • ion channels

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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