Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels
Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels
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Ib 类抗心律失常药物抑制心脏钠通道的分子基础
DOI：
10.1038/ncomms1351
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发表时间：
2011-06-01
影响因子：
16.6
通讯作者：
Ahern, Christopher A.
中科院分区：
文献类型：
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作者：
Pless, Stephan A.;Galpin, Jason D.;Ahern, Christopher A.
心脏钠通道是 I 类抗心律失常药物 (AAD) 治疗遗传性和获得性心律失常的既定治疗靶点。这些药物具有共同的靶受体，带有两个高度保守的芳香族侧链，并根据其对心电图的不同影响被 Vaughan-Williams 分类系统细分为 Ia-c 类。这些药物如何通过与共同受体结合而对心脏动作电位产生不同的影响？在这里，我们使用氟化苯丙氨酸衍生物来测试芳香族侧链的负电表面电位是否有助于六种 I 类 AAD 的抑制。令人惊讶的是，我们发现 Ib 类 AAD 通过强静电阳离子-π 相互作用结合，而 Ia 和 Ic 类 AAD 对这种相互作用的依赖明显较少。我们的数据为临床相关药物抑制心脏钠通道的药物-靶点相互作用提供了新的线索，并为 AAD 的定向设计提供信息。
Cardiac sodium channels are established therapeutic targets for the management of inherited and acquired arrhythmias by class I anti-arrhythmic drugs (AADs). These drugs share a common target receptor bearing two highly conserved aromatic side chains, and are subdivided by the Vaughan-Williams classification system into classes Ia-c based on their distinct effects on the electrocardiogram. How can these drugs elicit distinct effects on the cardiac action potential by binding to a common receptor? Here we use fluorinated phenylalanine derivatives to test whether the electronegative surface potential of aromatic side chains contributes to inhibition by six class I AADs. Surprisingly, we find that class Ib AADs bind via a strong electrostatic cation-pi interaction, whereas class Ia and Ic AADs rely significantly less on this interaction. Our data shed new light on drug-target interactions underlying the inhibition of cardiac sodium channels by clinically relevant drugs and provide information for the directed design of AADs.