Voltage-gated sodium channels (Navs) are promising targets for analgesic and antiepileptic therapies. Although specificity between Nav subtypes may be desirable to target specific neural types, such as nociceptors in pain, many broadly acting Nav inhibitors are clinically beneficial in neuropathic pain and epilepsy. Here, we present the first systematic characterization of vixotrigine, a Nav blocker. Using recombinant systems, we find that vixotrigine potency is enhanced in a voltage- and use-dependent manner, consistent with a state-dependent block of Navs. Furthermore, we find that vixotrigine potently inhibits sodium currents produced by both peripheral and central nervous system Nav subtypes, with use-dependent IC₅₀ values between 1.76 and 5.12 μM. Compared with carbamazepine, vixotrigine shows higher potency and more profound state-dependent inhibition but a similar broad spectrum of action distinct from Nav1.7- and Nav1.8-specific blockers. We find that vixotrigine rapidly inhibits Navs and prolongs recovery from the fast-inactivated state. In native rodent dorsal root ganglion sodium channels, we find that vixotrigine shifts steady-state inactivation curves. Based on these results, we conclude that vixotrigine is a broad-spectrum, state-dependent Nav blocker.

中文翻译：

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广谱电压门控钠通道阻滞剂Vixotrigine的表征

电压门控钠通道（Navs）是止痛和抗癫痫治疗的有希望的目标。尽管Nav亚型之间的特异性可能是靶向特定神经类型（例如疼痛中的伤害感受器）的理想方法，但许多作用广泛的Nav抑制剂在神经性疼痛和癫痫症方面具有临床优势。在这里，我们介绍了Nav阻滞剂vixotrigine的第一个系统表征。使用重组系统，我们发现维托三嗪效价以依赖于电压和使用的方式增强，与依赖于状态的Navs一致。此外，我们发现维托三嗪可有效抑制由周围和中枢神经系统Nav亚型产生的钠电流，并具有使用依赖性IC ₅₀值介于1.76和5.12μM之间。与卡马西平相比，维托三嗪显示出更高的效价和更强的状态依赖性抑制作用，但与Nav1.7和Nav1.8特异性阻滞剂不同，其作用范围相似。我们发现vixotrigine快速抑制Navs，并延长了从快速灭活状态的恢复时间。在本地啮齿动物的背根神经节钠通道中，我们发现vixotrigine移动稳态灭活曲线。根据这些结果，我们得出结论，维托三嗪是一种广谱的，依赖状态的Nav阻滞剂。