[3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen.
The pharmacological characteristics of [3H]dofetilide binding were examined in membranes prepared from human embryonic kidney (HEK293) cells stably expressing human ether-á-go-go related gene (HERG) K+ channels. The classIII antiarrhythmic compounds dofetilide, clofilium, 4'-[[1-[2-(6-methyl-2-pyridyl)ethyl]-4-piperidyl]carbonyl]methanesulfonanilide (E-4031), N-methyl-N-[2-[methyl-(1-methyl-1H-benzimidazol-2-yl)amino]ethyl]-4-[(methylsulfonyl)amino]benzene-sulfonamide (WAY-123,398) and d-sotalol all inhibited [3H]dofetilide binding. In addition, the structurally unrelated compounds pimozide, terfenadine and haloperidol, all of which prolong the QT interval in man, also inhibited binding. These data indicate that a [3H]dofetilide binding assay using HERG membranes may help identify compounds that prolong the QT interval.
Finlayson
K
K
Fujisawa Institute of Neuroscience, University of Edinburgh, 1 George Square, EH8 9JZ, Edinburgh, UK. Keith.Finlayson@ed.ac.uk
Turnbull
L
L
January
C T
CT
Sharkey
J
J
Kelly
J S
JS
D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D001667:Binding, Competitive; D027682:Cation Transport Proteins; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000378:metabolism*; D010868:Pimozide / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D013424:Sulfanilamides / Q000494:pharmacology; D013449:Sulfonamides / Q000378:metabolism*; D016593:Terfenadine / Q000494:pharmacology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014162:Transfection; D014316:Tritium; D000096926:Benzenesulfonamides
D000889:Anti-Arrhythmia Agents; D001562:Benzimidazoles; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006220:Haloperidol; D010627:Phenethylamines; D010868:Pimozide; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D000644:Quaternary Ammonium Compounds; D013424:Sulfanilamides; D013449:Sulfonamides; D016593:Terfenadine; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014316:Tritium; C072312:ERG protein, human; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; C073190:WAY 123398; D000096926:Benzenesulfonamides; C056528:LY 97241; C022799:clofilium; C063533:dofetilide