title: Comparative evaluation of hERG potassium channel blockade by antipsychotics.
abstract: Blockade of human ether-a-go-go-related gene (hERG) potassium channels is an undesirable activity of many drugs because it may be the primary cause for the prolongation of the QT interval, which appears to be associated with the induction of potentially life-threatening ventricular arrhythmias. Despite the fact that several antipsychotic drugs exert hERG-blocking activity that may underlie their propensity to cause electrocardiogram (ECG) abnormalities, including QT interval prolongation and associated ventricular arrhythmias, a considerable number of available typical and atypical antipsychotics have not been characterized for hERG-blocking activity. This study has evaluated the hERG-blocking activity of several of these antipsychotic drugs in human embryonic kidney cells (HEK293) stably transfected with the human recombinant hERG potassium channel and using a high throughput whole-cell patch-clamp technique to determine their respective IC(50) values. The ability of antipsychotics to competitively displace [(3)H]-astemizole binding from hERG-transfected HEK293 cells was also examined to properly establish the concentration range for testing in the subsequent patch clamp assays. The results showed that most of the tested antipsychotics effectively blocked the hERG channel in a dose-dependent manner, with IC(50) values ranging from 3.37 nM for the butyrophenone benperidol to >100 microM for the substituted benzamide sulpiride. Markedly, differential potencies were obtained depending on the chemical class, so that butyrophenones and diphenylbutylpiperidines emerged as the most potent hERG-blocking antipsychotics, while dibenzoxazepines and, particularly, substituted benzamides, exhibited the lowest activity. Because the hERG-blocking properties of drugs appear to be associated with their ability to prolong the QT interval, the present results will enable the establishment of the potential arrhythmogenic risk for each antipsychotic evaluated. Thus, their cardiotoxic risk will be discussed on the basis of their hERG-blocking properties and previous clinical data when available.
authors.affiliation: Department of Pharmacology, Prous Institute for Biomedical Research and Prous Science, Barcelona, Spain. jsilvestre@prous.com
authors.forename: J S
authors.initials: JS
authors.lastname: Silvestre
authors.forename: J R
authors.initials: JR
authors.lastname: Prous
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D016589:Astemizole / Q000378:metabolism; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006801:Humans; D026902:Potassium Channel Blockers / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D016589:Astemizole