基于GluN2B-NMDA受体拮抗作用的四氢吡咯并[2,1-b]喹唑啉类衍生物的设计、合成及活性研究

缺血性脑卒中严重威胁人类健康。N-甲基-D-天冬氨酸（NMDA）受体在缺血性脑卒中形成过程中起重要作用，其NR2B亚型是开发新型高选择性神经保护剂的关键靶标。在前期工作中，本课题组发现了一类结构新颖且具有良好神经保护活性的四氢吡咯并[2,1-b]喹唑啉类化合物，利用分子模拟方法和活性检测，初步证明了拮抗GluN2B-NMDA受体可能是其发挥神经保护活性的潜在作用机制。基于此，以GluN2B-NMDA蛋白结构和分子对接作用模式为指导，进行衍生物的设计与合成，并考察化合物的NMDA受体拮抗作用和抗自由基活性，以活性测试结果优化分子模拟活性位点的选取及修正化合物设计，建立准确的药效团和构效关系。最终，经多轮优化获得具有双重作用机制，疗效显著的新型GluN2B-NMDA受体拮抗剂，并初步评价其体内抗脑缺血活性，为开发治疗缺血性脑卒中的神经保护药物奠定基础。

Cerebral ischemia disease has severely threatened human's health. N-Methyl-D-Aspartete (NMDA) receptors are playing an important role in the process of ischemic cerebral. GluN2B-NMDA receptor is a key target during the development of novel scaffolds and high selectivity neuroprotective drugs. In previous work, we have found a class of novel tetrahydropyrrolo[2,1-b]quinazoline compounds, which have excellent neuroprotective activity. Using molecular simulation and activity evaluation method, we hypothesized that the mechanism of neuroprotective activity is due to antagonist GluN2B-NMDA receptor. Guided by the structure of GluN2B-NMDA receptor and molecular docking model, the derivatives were further designed and synthesized, then the antagonistic effect and anti-radicals activity of the compouds will be tested. Subsequently, bioevaluation provides evidence for the protein-binding sites modulation and derivative design again. Based on these results, accurate pharmacophores and structure-activity relationship can be established. Finally, we will obtain significant effective GluN2B-NMDA receptor antagonists with double mechanism of action, which will be tested the anti-cerebral ischemia effects in vivo. Our studies will lay a foundation for development of neuroprotective drugs in the treatment of cerebral ischemia disease.