hERG channel blockade by externally applied quaternary ammonium derivatives.

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.