[3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen

Eur J Pharmacol. 2001 Oct 26;430(1):147-8. doi: 10.1016/s0014-2999(01)01362-0.

Abstract

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.

MeSH terms

  • Anti-Arrhythmia Agents / metabolism*
  • Benzimidazoles / pharmacology
  • Binding, Competitive
  • Cation Transport Proteins*
  • Cell Line
  • Cell Membrane / metabolism*
  • DNA-Binding Proteins*
  • Drug Evaluation, Preclinical / methods
  • ERG1 Potassium Channel
  • Electrocardiography
  • Ether-A-Go-Go Potassium Channels
  • Haloperidol / pharmacology
  • Humans
  • Patch-Clamp Techniques
  • Phenethylamines / metabolism*
  • Pimozide / pharmacology
  • Potassium Channel Blockers
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • Potassium Channels, Voltage-Gated*
  • Quaternary Ammonium Compounds / pharmacology
  • Sulfanilamides / pharmacology
  • Sulfonamides / metabolism*
  • Terfenadine / pharmacology
  • Trans-Activators*
  • Transcriptional Regulator ERG
  • Transfection
  • Tritium

Substances

  • Anti-Arrhythmia Agents
  • Benzimidazoles
  • Cation Transport Proteins
  • DNA-Binding Proteins
  • ERG protein, human
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • KCNH6 protein, human
  • Phenethylamines
  • Potassium Channel Blockers
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Quaternary Ammonium Compounds
  • Sulfanilamides
  • Sulfonamides
  • Trans-Activators
  • Transcriptional Regulator ERG
  • Tritium
  • WAY 123398
  • Pimozide
  • LY 97241
  • Terfenadine
  • clofilium
  • Haloperidol
  • dofetilide