Abstract：
Voltage-gated sodium channel subtypes, Nav1.7, Nav1.8, and Nav1.9 are predominantly expressed in peripheral sensory neurons. Recent genetic studies have revealed that they are involved in pathological pain processing and that the blockade of Nav1.7, Nav1.8, or Nav1.9 will become a promising pharmacotherapy especially for neuropathic pain. A growing number of drug discovery programs have targeted either of the subtypes to obtain a selective inhibitor which can provide pain relief without affecting the cardiovascular and central nervous systems, though none of them has been approved yet. Here we describe the in vitro characteristics of ANP-230, a novel sodium channel blocker under clinical development. Surprisingly, ANP-230 was shown to block three pain-related subtypes, human Nav1.7, Nav1.8, and Nav1.9 with similar potency, but had only low inhibitory activity to human cardiac Nav1.5 channel and rat central Nav channels. The voltage clamp experiments using different step pulse protocols revealed that ANP-230 had a \"tonic block\" mode of action without state- and use-dependency. In addition, ANP-230 caused a depolarizing shift of the activation curve and decelerated gating kinetics in human Nav1.7-stably expressing cells. The depolarizing shift of activation curve was commonly observed in human Nav1.8-stably expressing cells as well as rat dorsal root ganglion neurons. These data suggested a quite unique mechanism of Nav channel inhibition by ANP-230. Finally, ANP-230 reduced excitability of rat dorsal root ganglion neurons in a concentration dependent manner. Collectively, these promising results indicate that ANP-230 could be a potent drug for neuropathic pain.
摘要：
电压门控钠通道亚型，Nav1.7、Nav1.8和Nav1.9主要在外周感觉神经元中表达。最近的遗传研究表明，它们参与病理性疼痛的处理，并且Nav1.7，Nav1.8或Nav1.9的阻断将成为有前途的药物疗法，尤其是对于神经性疼痛。越来越多的药物发现计划已针对任一亚型获得选择性抑制剂，该抑制剂可在不影响心血管和中枢神经系统的情况下缓解疼痛。尽管它们都没有被批准。在这里，我们描述了ANP-230的体外特征，这是一种正在临床开发中的新型钠通道阻滞剂。令人惊讶的是,显示ANP-230可阻断三种疼痛相关亚型，具有相似效力的人Nav1.7、Nav1.8和Nav1.9，但对人心脏Nav1.5通道和大鼠中枢Nav通道的抑制活性较低。使用不同阶跃脉冲协议的电压钳实验表明，ANP-230具有“强直阻滞”作用模式，没有状态和使用依赖性。此外,ANP-230在人Nav1.7稳定表达细胞中引起激活曲线的去极化偏移并减慢门控动力学。在人Nav1.8稳定表达细胞以及大鼠背根神经节神经元中通常观察到激活曲线的去极化位移。这些数据表明ANP-230抑制Nav通道的非常独特的机制。最后,ANP-230以浓度依赖的方式降低大鼠背根神经节神经元的兴奋性。总的来说，这些有希望的结果表明ANP-230可能是治疗神经性疼痛的有效药物.
