HERG channel blockade by externally applied quaternary ammonium derivatives

Kee Hyun Choi, Chiman Song, Dongyun Shin, Sungnam Park

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The human ether-à-go-go related gene potassium channel is a key player in cardiac rhythm regulation, thus being an important subject for a cardiac toxicity test. Ever since human ether-à-go-go related gene channel inhibition-related cardiac arrest was proven to be fatal, numerous numbers of data on human ether-à-go-go related gene channel inhibition have been piled up. However, there has been no quantitative study on human ether-à-go-go related gene channel inhibition by quaternary ammonium derivatives, well-known potassium channel blockers. Here, we present human ether-à-go-go related gene channel blockade by externally applied quaternary ammonium derivatives using automated whole-cell patch-clamp recordings as well as ab initio quantum calculations. The inhibitory constants and the relative binding energies for human ether-à-go-go related gene channel inhibition were obtained from quaternary ammoniums with systematically varied head and tail groups, indicating that more hydrophobic quaternary ammoniums have higher affinity blockade while cation-π interactions or size effects are not a deterministic factor for human ether-à-go-go related gene channel inhibition by quaternary ammoniums. Further studies on the effect of quaternary ammoniums on human ether-à-go-go related gene channel inactivation implied that hydrophobic quaternary ammoniums either with a longer tail group or with a bigger head group than tetraethylammonium permeate the cell membrane to easily access the high-affinity internal binding site in human ether-à-go-go related gene channel and exert stronger blockade. These results may be informative for the rational drug design to avoid cardiac toxicity.

Original languageEnglish
Pages (from-to)1560-1566
Number of pages7
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1808
Issue number6
DOIs
Publication statusPublished - 2011 Jun 1

Fingerprint

Ammonium Compounds
Ether
Genes
Derivatives
Toxicity
Tail
Potassium Channel Blockers
Toxicity Tests
Tetraethylammonium
Drug Design
Potassium Channels
Clamping devices
Gene Silencing
Cell membranes
Heart Arrest
Binding energy
Cations
Binding Sites
Cell Membrane
Pharmaceutical Preparations

Keywords

  • Cation-π interaction
  • hERG channel
  • Hydrophobicity
  • Inactivation
  • Quaternary ammonium

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Biophysics

Cite this

HERG channel blockade by externally applied quaternary ammonium derivatives. / Choi, Kee Hyun; Song, Chiman; Shin, Dongyun; Park, Sungnam.

In: Biochimica et Biophysica Acta - Biomembranes, Vol. 1808, No. 6, 01.06.2011, p. 1560-1566.

Research output: Contribution to journalArticle

Choi, Kee Hyun ; Song, Chiman ; Shin, Dongyun ; Park, Sungnam. / HERG channel blockade by externally applied quaternary ammonium derivatives. In: Biochimica et Biophysica Acta - Biomembranes. 2011 ; Vol. 1808, No. 6. pp. 1560-1566.
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