Brochu Richard M, Dick Ivy E, Tarpley Jason W, McGowan Erin, Gunner David, Herrington James, Shao Pengcheng P, Ok Dong, Li Chunshi, Parsons William H, Stump Gary L, Regan Christopher P, Lynch Joseph J, Lyons Kathryn A, McManus Owen B, Clark Samantha, Ali Zahid, Kaczorowski Gregory J, Martin William J, Priest Birgit T
Department of Ion Channels, Merck Research Laboratories, Rahway, NJ, USA..
Mol Pharmacol. 2006 Mar;69(3):823-32. doi: 10.1124/mol.105.018127. Epub 2005 Nov 21.
Several sodium channel blockers are used clinically to treat neuropathic pain. However, many patients fail to achieve adequate pain relief from these highly brain-penetrant drugs because of dose-limiting central nervous system side effects. Here, we describe the functional properties of trans-N-{[2'-(aminosulfonyl)biphenyl-4-yl]methyl}-N-methyl-N'-[4-(trifluoromethoxy)benzyl]cyclopentane-1,2-dicarboxamide (CDA54), a peripherally acting sodium channel blocker. In whole-cell electrophysiological assays, CDA54 blocked the inactivated states of hNa(V)1.7 and hNa(V)1.8, two channels of the peripheral nervous system implicated in nociceptive transmission, with affinities of 0.25 and 0.18 microM, respectively. CDA54 displayed similar affinities for the tetrodotoxin-resistant Na+ current in small-diameter mouse dorsal root ganglion neurons. Peripheral nerve injury causes spontaneous electrical activity in normally silent sensory neurons. CDA54 inhibited these injury-induced spontaneous action potentials at concentrations 10-fold lower than those required to block normal A- and C-fiber conduction. Consistent with the selective inhibition of injury-induced firing, CDA54 (10 mg/kg p.o.) significantly reduced behavioral signs of neuropathic pain in two nerve injury models, whereas the same dose of CDA54 did not affect acute nociception or motor coordination. In anesthetized dogs, CDA54, at plasma concentrations of 6.7 microM, had no effect on cardiac electrophysiological parameters including conduction. Thus, the peripheral nerve sodium channel blocker CDA54 selectively inhibits sensory nerve signaling associated with neuropathic pain.
几种钠通道阻滞剂在临床上用于治疗神经性疼痛。然而，由于剂量限制性中枢神经系统副作用，许多患者使用这些具有高脑渗透性的药物后未能获得充分的疼痛缓解。在此，我们描述了一种外周作用的钠通道阻滞剂反式-N-{[2'-(氨磺酰基)联苯-4-基]甲基}-N-甲基-N'-[4-(三氟甲氧基)苄基]环戊烷-1,2-二甲酰胺（CDA54）的功能特性。在全细胞膜片钳电生理实验中，CDA54阻断了hNa(V)1.7和hNa(V)1.8这两种参与伤害性感受传递的外周神经系统通道的失活状态，亲和力分别为0.25和0.18微摩尔。CDA54对小直径小鼠背根神经节神经元中的河豚毒素抗性Na+电流表现出相似的亲和力。外周神经损伤会导致正常情况下沉默的感觉神经元出现自发放电活动。CDA54抑制这些损伤诱导的自发放电动作电位的浓度比阻断正常A纤维和C纤维传导所需浓度低10倍。与对损伤诱导放电的选择性抑制一致，CDA54（口服10毫克/千克）在两种神经损伤模型中显著减轻了神经性疼痛的行为体征，而相同剂量的CDA54不影响急性痛觉或运动协调性。在麻醉犬中，血浆浓度为6.7微摩尔的CDA54对包括传导在内的心脏电生理参数没有影响。因此，外周神经钠通道阻滞剂CDA54选择性抑制与神经性疼痛相关的感觉神经信号传导。
