Beijing Institute of Biotechnology, Beijing 100071, China.
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Mar Drugs. 2021 Jan 19;19(1):44. doi: 10.3390/md19010044.
-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist con-T[M8Q](a conantokin-T variant) that potently inhibits the naloxone-induced jumping and conditioned place preference of morphine-dependent mice at nmol/kg level, 100-fold higher than ifenprodil, a classical NMDAR NR2B antagonist. Con-T[M8Q] displays no significant impacts on coordinated locomotion function, spontaneous locomotor activity, and spatial memory mice motor function at the dose used. Further molecular mechanism experiments demonstrate that con-T[M8Q] effectively inhibited the transcription and expression levels of signaling molecules related to NMDAR NR2B subunit in hippocampus, including NR2B, p-NR2B, CaMKII-α, CaMKII-β, CaMKIV, pERK, and c-fos. The high efficacy and low side effects of con-T[M8Q] make it a good lead compound for the treatment of opiate dependence and for the reduction of morphine usage.
-甲基-D-天冬氨酸受体（NMDAR）拮抗剂已被发现可有效抑制吗啡依赖。然而，具有低副作用的 NMDAR GluN2B 选择性拮抗剂的发现仍然具有挑战性。在本研究中，我们报告了一种选择性 NMDAR GluN2B 拮抗剂 con-T[M8Q]（一种 conantokin-T 变体），它在纳洛酮诱导的吗啡依赖小鼠跳跃和条件性位置偏爱中具有很强的抑制作用，在 nmol/kg 水平下的效力比ifenprodil（一种经典的 NMDAR NR2B 拮抗剂）高 100 倍。Con-T[M8Q]在使用的剂量下对协调运动功能、自发运动活动和空间记忆无明显影响。进一步的分子机制实验表明，Con-T[M8Q]有效抑制了海马中与 NMDAR NR2B 亚基相关的信号分子的转录和表达水平，包括 NR2B、p-NR2B、CaMKII-α、CaMKII-β、CaMKIV、pERK 和 c-fos。Con-T[M8Q]的高效性和低副作用使其成为治疗阿片类药物依赖和减少吗啡使用的良好先导化合物。
