Department of Neurobiology (P.V., A.F., S.J., H.-X.B.Z., T.O., B.P.B.) and Laboratory of Systems Pharmacology and Harvard Program in Therapeutics (X.M.), Harvard Medical School, Boston, Massachusetts.
Department of Neurobiology (P.V., A.F., S.J., H.-X.B.Z., T.O., B.P.B.) and Laboratory of Systems Pharmacology and Harvard Program in Therapeutics (X.M.), Harvard Medical School, Boston, Massachusetts
Mol Pharmacol. 2024 Nov 18;106(6):298-308. doi: 10.1124/molpharm.124.000944.
Nav1.8 sodium channels (Nav1.8) are an attractive therapeutic target for pain because they are prominent in primary pain-sensing neurons with little expression in most other kinds of neurons. Recently, two Nav1.8-targeted compounds, VX-150 and VX-548, have shown efficacy in clinical trials for reducing pain. We examined the characteristics of Nav1.8 inhibition by these compounds. The active metabolite form of VX-150 (VX-150m) inhibited human Nav1.8 channels with an IC of 15 nM. VX-548 (suzetrigine) was even more potent (IC 0.27 nM). Both VX-150m and VX-548 had the unusual property of "reverse use-dependence," whereby inhibition could be relieved by repetitive depolarizations, a property seen before with another Nav1.8 inhibitor, A-887826. The relief of VX-548 inhibition by large depolarizations occurred with a time constant of ∼40 milliseconds that was not concentration-dependent. Reinhibition at negative voltages occurred with a rate that was nearly proportional to drug concentration, consistent with the idea that relief of inhibition reflects dissociation of drug from the channel and reinhibition reflects rebinding. The relief of inhibition by depolarization suggests a remarkably strong and unusual state-dependence for both VX-150m and VX-548, with very weak binding to channels with fully activated voltage sensors despite very tight binding to channels with voltage sensors in the resting state. SIGNIFICANCE STATEMENT: The Nav1.8 sodium channel (Nav1.8) is a current target for new drugs for pain. This work describes the potency, selectivity, and state-dependent characteristics of inhibition of Nav1.8 channels by VX-150 and VX-548, compounds that have recently shown efficacy for relief of pain in clinical trials but whose mechanism of interaction with channels has not been described. The results show that the compounds share an unusual property whereby inhibition is relieved by depolarization, demonstrating a state-dependence different from most sodium channel inhibitors.
Nav1.8 钠离子通道 (Nav1.8) 是治疗疼痛的一个有吸引力的治疗靶点，因为它们在主要的疼痛感觉神经元中表现突出，而在大多数其他类型的神经元中表达很少。最近，两种靶向 Nav1.8 的化合物 VX-150 和 VX-548 在临床试验中显示出减轻疼痛的疗效。我们研究了这些化合物对 Nav1.8 抑制的特性。VX-150 的活性代谢产物形式 (VX-150m) 对人 Nav1.8 通道的抑制作用的 IC 为 15 nM。VX-548（苏泽替尼）甚至更有效（IC 0.27 nM）。VX-150m 和 VX-548 都具有“反向使用依赖性”的不寻常特性，即通过重复去极化可以缓解抑制作用，这种特性以前在另一种 Nav1.8 抑制剂 A-887826 中也见过。大去极化引起的 VX-548 抑制的缓解作用具有约 40 毫秒的时间常数，且与浓度无关。在负电压下再抑制时，其速率几乎与药物浓度成正比，这与抑制作用的缓解反映药物与通道的解离，再抑制反映药物与通道的重新结合的观点一致。去极化引起的抑制作用的缓解表明，对于 VX-150m 和 VX-548 来说，这是一种非常强烈和不寻常的状态依赖性，尽管对处于静止状态的电压传感器的通道具有非常紧密的结合，但对充分激活的电压传感器的通道具有非常弱的结合。意义陈述：Nav1.8 钠离子通道 (Nav1.8) 是治疗疼痛的新药靶点。这项工作描述了 VX-150 和 VX-548 对 Nav1.8 通道的抑制作用的效力、选择性和状态依赖性特征，这两种化合物最近在临床试验中显示出缓解疼痛的疗效，但它们与通道相互作用的机制尚未描述。结果表明，这些化合物具有一种不寻常的特性，即抑制作用可通过去极化缓解，表明其状态依赖性与大多数钠离子通道抑制剂不同。
