Allosteric modulators of the hERG K(+) channel: radioligand binding assays reveal allosteric characteristics of dofetilide analogs.

摘要: Drugs that block the cardiac K(+) channel encoded by human ether-a-go-go gene (hERG) have been associated with QT interval prolongation leading to proarrhythmia, and in some cases, sudden death. Because of special structural features hERG channel, it has become a promiscuous target interacts pharmaceuticals widely varying chemical structures reason for concern pharmaceutical industry. The diversity suggests multiple binding sites are available on possible allosteric interactions between them. In present study, three reference compounds nine previously disclosed series were evaluated their effects [(3)H]astemizole [(3)H]dofetilide channel. LUF6200 was identified as an inhibitor dissociation assays both radioligands, yielding similar EC50 values low micromolar range. However, potassium ions increased two radioligands concentration-dependent manner, not significantly different, indicating behaved enhancers. Furthermore, addition resulted leftward shift response curve, suggesting positive cooperativity distinct conclusion, our investigations provide evidence modulation which is discussed light findings other ion channels.