hERG channel blockade by externally applied quaternary ammonium derivatives

Title
hERG channel blockade by externally applied quaternary ammonium derivatives
Authors
최기현송치만신동윤박성남
Keywords
hERG channel; Quaternary ammonium; Hydrophobicity; Cation-π interaction; Inactivation
Issue Date
2011-06
Publisher
Biochimica et biophysica acta, Biomembranes
Citation
VOL 1808, NO 6, 1560-1566
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-gogo 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.
URI
http://pubs.kist.re.kr/handle/201004/39492
ISSN
0005-2736
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KIST Publication > Article
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