Key Laboratory of Structure-Based Drug Design& Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
Department of General Hospital of Northern Theater Command, Shenyang, PR China.
Eur J Med Chem. 2019 Nov 15;182:111654. doi: 10.1016/j.ejmech.2019.111654. Epub 2019 Aug 28.
A series of 1-benzyl-5-oxopyrrolidine-2-carboximidamide derivatives were designed and synthesized. Their protective activities against N-methyl-d-aspartic acid (NMDA)-induced cytotoxicity were investigated in vitro. All of the compounds exhibited neuroprotective activities, especially 12k, which showed higher potency than reference compound 1 (ifenprodil). Further investigation showed that 12k could attenuate Ca influx and suppress the NR2B upregulation induced by NMDA. The docking results indicated that 12k could fit well into binding site of 1 in the NR2B-NMDA receptor. Additionally, 12k exhibited excellent metabolic stability. Furthermore, the results of behavioral tests showed that compound 12k could significantly improve learning and memory in vivo. These results suggested that 12k is a promising neuroprotective drug candidate and that the NR2B-NMDA receptor is a potential target of 12k.
设计并合成了一系列 1-苄基-5-氧代吡咯烷-2-甲脒衍生物。在体外研究了它们对 N-甲基-D-天冬氨酸（NMDA）诱导的细胞毒性的保护作用。所有化合物均表现出神经保护活性，特别是 12k，其活性高于对照化合物 1（ifenprodil）。进一步的研究表明，12k 可以减弱 Ca 内流并抑制 NMDA 诱导的 NR2B 上调。对接结果表明，12k 可以很好地适应 NR2B-NMDA 受体中 1 的结合位点。此外，12k 表现出优异的代谢稳定性。此外，行为测试结果表明，化合物 12k 可以显著改善体内学习和记忆能力。这些结果表明，12k 是一种有前途的神经保护药物候选物，NR2B-NMDA 受体是 12k 的潜在靶点。
