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
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Anti-Arrhythmia Agents / metabolism*
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Benzimidazoles / pharmacology
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Binding, Competitive
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Cation Transport Proteins*
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Cell Line
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Cell Membrane / metabolism*
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DNA-Binding Proteins*
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Drug Evaluation, Preclinical / methods
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ERG1 Potassium Channel
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Electrocardiography
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Ether-A-Go-Go Potassium Channels
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Haloperidol / pharmacology
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Humans
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Patch-Clamp Techniques
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Phenethylamines / metabolism*
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Pimozide / pharmacology
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Potassium Channel Blockers
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Potassium Channels / genetics
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Potassium Channels / metabolism*
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Potassium Channels, Voltage-Gated*
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Quaternary Ammonium Compounds / pharmacology
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Sulfanilamides / pharmacology
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Sulfonamides / metabolism*
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Terfenadine / pharmacology
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Trans-Activators*
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Transcriptional Regulator ERG
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Transfection
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Tritium
Substances
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Anti-Arrhythmia Agents
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Benzimidazoles
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Cation Transport Proteins
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DNA-Binding Proteins
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ERG protein, human
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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KCNH6 protein, human
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Phenethylamines
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Potassium Channel Blockers
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Potassium Channels
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Potassium Channels, Voltage-Gated
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Quaternary Ammonium Compounds
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Sulfanilamides
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Sulfonamides
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Trans-Activators
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Transcriptional Regulator ERG
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Tritium
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WAY 123398
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Pimozide
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LY 97241
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Terfenadine
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clofilium
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Haloperidol
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dofetilide