Allosteric modulators of the hERG Kp>+p> channel: Radioligand binding assays reveal allosteric characteristics of dofetilide analogs

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• 作者：Zhiyi Yu ; Elisabeth Klaasse ; Laura H. Heitman ; Adriaan P. IJzerman
• 关键词：hERG K+ channel ; Allosteric modulator ; LUF6200 ; Potassium ions ; [3H]astemizole ; [3H]dofetilide
• 刊名：Toxicology and Applied Pharmacology
• 出版年：1 January, 2014
• 年：2014
• 卷：274
• 期：1
• 页码：78-86
• 全文大小：974 K

文摘

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