Discovery of a retigabine derivative that inhibits KCNQ2 potassium channels

Hai Ning Hu, Ping Zheng Zhou, Fei Chen, Min Li, Fa Jun Nan, Zhao Bing Gao

Research output: Contribution to journalArticlepeer-review

Abstract

Aim: Retigabine, an activator of KCNQ2-5 channels, is currently used to treat partial-onset seizures. The aim of this study was to explore the possibility that structure modification of retigabine could lead to novel inhibitors of KCNQ2 channels, which were valuable tools for KCNQ channel studies. Methods: A series of retigabine derivatives was designed and synthesized. KCNQ2 channels were expressed in CHO cells. KCNQ2 currents were recorded using whole-cell voltage clamp technique. Test compound in extracellular solution was delivered to the recorded cell using an ALA 8 Channel Solution Exchange System. Results: A total of 23 retigabine derivatives (HN31-HN410) were synthesized and tested electrophysiologically. Among the compounds, HN38 was the most potent inhibitor of KCNQ2 channels (its IC 50 value=0.10±0.05 μmol/L), and was 7-fold more potent than the classical KCNQ inhibitor XE991. Further analysis revealed that HN38 (3 μmol/L) had no detectable effect on channel activation, but accelerated deactivation at hyperpolarizing voltages. In contrast, XE991 (3 μmol/L) did not affect the kinetics of channel activation and deactivation. Conclusion: The retigabine derivative HN38 is a potent KCNQ2 inhibitor, which differs from XE991 in its influence on the channel kinetics. Our study provides a new strategy for the design and development of potent KCNQ2 channel inhibitors.

Original languageEnglish (US)
Pages (from-to)1359-1366
Number of pages8
JournalActa Pharmacologica Sinica
Volume34
Issue number10
DOIs
StatePublished - Oct 2013

Keywords

  • CHO cell
  • HN38
  • KCNQ2 channel
  • Retigabine
  • Structure modification
  • Whole-cell recording
  • XE991

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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