title: Identification of quaternary ammonium compounds as potent inhibitors of hERG potassium channels.
abstract: The human ether-a-go-go-related gene (hERG) channel, a member of a family of voltage-gated potassium (K(+)) channels, plays a critical role in the repolarization of the cardiac action potential. The reduction of hERG channel activity as a result of adverse drug effects or genetic mutations may cause QT interval prolongation and potentially leads to acquired long QT syndrome. Thus, screening for hERG channel activity is important in drug development. Cardiotoxicity associated with the inhibition of hERG channels by environmental chemicals is also a public health concern. To assess the inhibitory effects of environmental chemicals on hERG channel function, we screened the National Toxicology Program (NTP) collection of 1408 compounds by measuring thallium influx into cells through hERG channels. Seventeen compounds with hERG channel inhibition were identified with IC(50) potencies ranging from 0.26 to 22μM. Twelve of these compounds were confirmed as hERG channel blockers in an automated whole cell patch clamp experiment. In addition, we investigated the structure-activity relationship of seven compounds belonging to the quaternary ammonium compound (QAC) series on hERG channel inhibition. Among four active QAC compounds, tetra-n-octylammonium bromide was the most potent with an IC(50) value of 260nM in the thallium influx assay and 80nM in the patch clamp assay. The potency of this class of hERG channel inhibitors appears to depend on the number and length of their aliphatic side-chains surrounding the charged nitrogen. Profiling environmental compound libraries for hERG channel inhibition provides information useful in prioritizing these compounds for cardiotoxicity assessment in vivo.
authors.affiliation: NIH Chemical Genomics Center, National Institutes of Health, Bethesda, MD 20892-3370, USA. mxia@mail.nih.gov
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
authors.forename: Sampada A
authors.initials: SA
authors.lastname: Shahane
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: Steven A
authors.initials: SA
authors.lastname: Titus
authors.forename: Enoch
authors.initials: E
authors.lastname: Shum
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Kristine L
authors.initials: KL
authors.lastname: Witt
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tice
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D018408:Patch-Clamp Techniques; D000644:Quaternary Ammonium Compounds / Q000009:adverse effects / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D000644:Quaternary Ammonium Compounds