Department of Anesthesiology, University of British Columbia, 2350 Health Science Mall, Vancouver, British Columbia, V6T 1Z3 Canada.
Nat Commun. 2011 Jun 14;2:351. doi: 10.1038/ncomms1351.
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.
心脏钠离子通道是一类治疗遗传性和获得性心律失常的药物靶点，该类药物通过 I 类抗心律失常药物（AAD）来实现。这些药物具有共同的靶受体，该受体具有两个高度保守的芳基侧链，根据其对心电图的不同影响， Vaughan-Williams 分类系统将其分为 Ia-c 类。这些药物如何通过与共同的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基侧链的负表面电势是否有助于 6 种 I 类 AAD 的抑制作用。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 则显著依赖于这种相互作用。我们的数据为临床相关药物抑制心脏钠离子通道的药物-靶标相互作用提供了新的见解，并为 AAD 的定向设计提供了信息。
