title: hERG channel blockade by externally applied quaternary ammonium derivatives.
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.
authors.affiliation: Life/Health Division, Korea Institute of Science and Technology, 39-1 Hawolgok-Dong, Seongbuk-Gu, Seoul 136-791, South Korea. keehyun@kist.re.kr
authors.forename: Kee-Hyun
authors.initials: KH
authors.lastname: Choi
authors.forename: Chiman
authors.initials: C
authors.lastname: Song
authors.forename: Dongyun
authors.initials: D
authors.lastname: Shin
authors.forename: Sungnam
authors.initials: S
authors.lastname: Park
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D019789:Tetraethylammonium / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D000644:Quaternary Ammonium Compounds; C052377:tetrapropylammonium; D019789:Tetraethylammonium