Biogen, Cambridge, Massachusetts (C.A.H., H.N.); Charles River Laboratories Cleveland, Inc., Cleveland, Ohio (Y.K.); Neuroservice, Aix-en-Provence, France (A.S., A.B., B.B.); and Department of Comparative Medicine, Yale University, New Haven, Connecticut (M.H.)
Biogen, Cambridge, Massachusetts (C.A.H., H.N.); Charles River Laboratories Cleveland, Inc., Cleveland, Ohio (Y.K.); Neuroservice, Aix-en-Provence, France (A.S., A.B., B.B.); and Department of Comparative Medicine, Yale University, New Haven, Connecticut (M.H.).
Mol Pharmacol. 2021 Jan;99(1):49-59. doi: 10.1124/molpharm.120.000079.
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 IC 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. SIGNIFICANCE STATEMENT: Vixotrigine blocks both peripheral and central voltage-gated sodium channel subtypes. Neurophysiological approaches in recombinant systems and sensory neurons suggest this block is state-dependent.
电压门控钠离子通道（Navs）是治疗疼痛和癫痫的有前途的靶点。尽管针对特定的神经类型（如疼痛中的伤害感受器）可能需要Nav 亚型之间的特异性，但许多广泛作用的 Nav 抑制剂在神经病理性疼痛和癫痫中具有临床益处。在这里，我们首次系统地描述了 vixotrigine，一种 Nav 阻断剂。使用重组系统，我们发现 vixotrigine 的效力以电压和使用依赖性方式增强，这与 Navs 的状态依赖性阻断一致。此外，我们发现 vixotrigine 能有效抑制外周和中枢神经系统 Nav 亚型产生的钠电流，使用依赖性 IC 值在 1.76 和 5.12 μM 之间。与卡马西平相比，vixotrigine 具有更高的效力和更深刻的状态依赖性抑制作用，但与 Nav1.7 和 Nav1.8 特异性阻断剂相比，具有相似的广谱作用。我们发现 vixotrigine 可迅速抑制 Navs 并延长从快速失活状态的恢复时间。在天然啮齿动物背根神经节钠离子通道中，我们发现 vixotrigine 会改变稳态失活曲线。基于这些结果，我们得出结论，vixotrigine 是一种广谱的、状态依赖性的 Nav 阻断剂。
Vixotrigine 可阻断外周和中枢电压门控钠离子通道亚型。重组系统和感觉神经元中的神经生理学方法表明，这种阻断是状态依赖性的。
