Inhibition of HERG potassium channels by domiphen bromide and didecyl dimethylammonium bromide

Eur J Pharmacol. 2014 Aug 15:737:202-9. doi: 10.1016/j.ejphar.2014.05.002. Epub 2014 May 15.

Abstract

Domiphen bromide and didecyl dimethylammonium bromide were widely used environmental chemicals with potent activity on blockade of human ether-a-go-go related gene (HERG) channels. But the mechanism of their action is not clear. The kinetics of block of HERG channels by domiphen bromide and didecyl dimethylammonium bromide was studied in order to characterize the inhibition of HERG currents by these quaternary ammonium compounds (QACs). Domiphen bromide and didecyl dimethylammonium bromide inhibited HERG channel currents in a dose-dependent manner with IC50 values of 9nM and 5nM, respectively. Block of HERG channel by domiphen bromide and didecyl dimethylammonium bromide was voltage-dependent and use-dependent. Domiphen bromide and didecyl dimethylammonium bromide caused substantial negative shift of the activation curves, accelerated activated process, but had no effects on the deactivation and reactivation processes. The docking models implied that these two compounds bound to PAS domain of HERG channels and inhibited its function. Our data demonstrated that domiphen bromide and didecyl dimethylammonium bromide blocked the HERG channel with a preference for the activated channel state.

Keywords: Didecyl dimethylammonium bromide (PubChem CID: 16957); Domiphen bromide (PubChem CID: 10866); HERG channel; Patch clamp; Quaternary ammonium compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Electrophysiological Phenomena / drug effects
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Ether-A-Go-Go Potassium Channels / chemistry
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Humans
  • Kinetics
  • Molecular Docking Simulation
  • Potassium Channel Blockers / metabolism
  • Potassium Channel Blockers / pharmacology*
  • Protein Structure, Tertiary
  • Quaternary Ammonium Compounds / metabolism
  • Quaternary Ammonium Compounds / pharmacology*

Substances

  • Ether-A-Go-Go Potassium Channels
  • Potassium Channel Blockers
  • Quaternary Ammonium Compounds
  • domiphen
  • didecyldimethylammonium