We have previously reported that the microtubule-associated collapsin response mediator protein 2 (CRMP2) is necessary for the expression of chronic pain. CRMP2 achieves this control of nociceptive signaling by virtue of its ability to regulate voltage-gated calcium and sodium channels. To date, however, no drugs exist that target CRMP2. Recently, the small molecule edonerpic maleate (1 -{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate), a candidate therapeutic for Alzheimer’s disease was reported to be a novel CRMP2 binding compound with the potential to decrease its phosphorylation level in cortical tissues in vivo. Here we sought to determine the mechanism of action of edonerpic maleate and test its possible effect in a rodent model of chronic pain. We observed: (i) no binding between human CRMP2 and edonerpic maleate; (ii) edonerpic maleate had no effect on CRMP2 expression and phosphorylation in dorsal root ganglion (DRG) neurons; (iii) edonerpic maleate-decreased calcium but increased sodium current density in DRG neurons; and (iv) edonerpic maleate was ineffective in reversing post-surgical allodynia in male and female mice. Thus, while CRMP2 inhibiting compounds remain a viable strategy for developing new mechanism-based pain inhibitors, edonerpic maleate is an unlikely candidate.

我们以前曾报道过，微管相关的胶原蛋白反应介导蛋白2（CRMP2）对于表达慢性疼痛是必需的。CRMP2凭借其调节电压门控钙和钠通道的能力，实现了对伤害性信号传导的控制。但是，迄今为止，尚不存在靶向CRMP2的药物。近来，据报道小分子埃德纳比马来酸酯（1- {3- [2-（1-（苯并噻吩-5-基）乙氧基]丙基}氮杂环丁烷-3-醇马来酸酯）是新型的CRMP2。具有降低体内磷酸化水平的潜在化合物。在这里，我们试图确定马来酸马来酸的作用机理，并在啮齿动物慢性疼痛模型中测试其可能的作用。我们观察到：（i）人CRMP2与马来酸马来酸烯丙酯之间没有结合；（ii）马来酸马来酸酯对背根神经节（DRG）神经元中CRMP2的表达和磷酸化没有影响；（iii）马来酸edonerpic降低了钙，但增加了DRG神经元的钠电流密度；（iv）马来酸edonerpic无法逆转雄性和雌性小鼠的手术后异常性疼痛。因此，尽管抑制CRMP2的化合物仍然是开发新的基于机理的止痛药的可行策略，但马来酸马来酸埃德美比不可能。