新型选择性GluN2B-NMDA受体拮抗剂的发现及其神经保护与抗脑缺血作用研究

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。目前，选择性GluN2B-NMDA受体拮抗剂通常由于靶向性不强，副作用大而止步于临床。近期，该靶标的第二个配体结合区域的发现，为该类拮抗剂的研发带来了新的契机。申请人前期利用理论计算首次对该区域进行了解析，并基于靶标结构中关键残基的差异进行精准药物设计，据此设计并发现了5类结构骨架的高活性小分子化合物。本项目拟以上述活性小分子为先导化合物，开展结构优化及神经保护与抗脑缺血作用研究，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，经多轮优化获得活性高且成药性好的新型选择性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高选择性神经保护药物奠定基础。

N-Methyl-D-Aspartate (NMDA) receptor is playing an important role in the process of ischemic cerebral. GluN2B-NMDAR is a key target during the development of novel scaffolds and high selective neuroprotective drugs. Most of selective GluN2B-NMDA receptor antagonists are usually stopped in clinical practice due to their low receptor selectivities and the side effects. Recently, the discovery of the second binding region of this target has brought a new opportunity for the development of this type of antagonists. In our previous studies, we had analyzed the action mode of second binding region by theoretical calculation for the first time. Based on precision drug design strategy, the studies will focus on modification of the lead compound according to the “Hot-spot residues” and five kinds of high-activity small molecule compounds with structural skeletons were designed and found. In this proposal, we will use the previously identified high-activity small molecule compounds as our lead compounds to carry out research on structural optimization, neuroprotection and anti-ischemic effects. 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 novel selective GluN2B-NMDA receptor antagonists with significant effect and good drugability properties for preclinical research, which will be tested the anti-cerebral ischemia effects in vivo. Our studies will lay a foundation for development of high selective neuroprotective drugs in the treatment of cerebral ischemia disease.