基于NMDA受体NR2B亚单位的C21甾体化合物构效关系、结构优化及抗抑郁研究

Depression is a common mental disease. NMDA receptor NR2B subunit may serve as a viable therapeutical target for the development of fast-acting antidepressants and antidepressants for treatment-resistant depression. Our previous research showed that the C21 steroidal compounds from plants possessed antidepressant action and their antidepressant mechanism maybe target to NMDA receptor NR2B subunit based on the molecular simulation between 27 natural C21 steroidal compounds including three common nucleus skeleton and GR, CRF1, NMDA receptors,respectively. In this project leading compounds could be discovered by structure-relationship analysis of selective antagonism of 27 C21 steroidal compounds on NMDA receptor NR2B subunit, combined with the molecular simulation between 27 C21 steroidal compounds and NMDA receptor. Meanwhile, pharmacophore model of selective antagonist of NMDA receptor NR2B subunit was constructed and will be revised by the results of activities in vitro on NMDA receptor. By the revised pharmacophore model, structural optimization of leading compounds will be done and a series of new C21 steroidal compounds will be devised and synthetized. The new compounds will be assayed their selective antagonistic activities on NMDA receptor NR2B subunit in vitro and evaluated their antidepressant effect in vivo. The novel NR2B-selective NMDA receptor antagonist possessing antidepressant effect will be expected.

抑郁症是一种常见的精神障碍性疾病。NMDA受体NR2B亚单位选择性拮抗剂可能成为速效抗抑郁药物和难治性抑郁症的治疗药物。前期研究发现天然C21甾体化合物具有抗抑郁作用，对包含有三种常见基本母核骨架的27个天然C21甾体化合物可能的抗抑郁靶点GR、CRF1、NMDA受体的分子模拟，结果显示它们很可能是通过NMDA受体NR2B亚单位达到抗抑郁的作用。本项目通过27个化合物和NMDA受体NR2B亚单位选择性拮抗构效关系分析，结合化合物与NMDA受体的分子模拟发现先导化合物；同时我们构建了NMDA受体NR2B亚单位拮抗剂的药效团模型，结合体外受体拮抗活性对药效团模型进行修正。以修正后的药效团模型指导活性先导化合物的结构优化，设计、合成新的C21甾体衍生物，并对其进行体外NMDA受体NR2B亚单位选择性拮抗活性评价和体内的抗抑郁作用研究，以期获得具有抗抑郁作用的新颖NMDA受体NR2B亚单位拮抗剂。

抑郁症是一种常见的精神障碍性疾病。NMDA受体NR2B亚单位拮抗剂可能成为速效抗抑郁药物和难治性抑郁症的治疗药物。本项目采用现代分离技术从萝藦科植物中分离获得一系列的C21甾体化合物52个，其中新化合物17个，并进行衍生化，然后以计算机分子模拟和NR2B结合、功能实验筛选活性化合物并进行构效关系分析，获得一个具有一定NMDA受体 NR2B拮抗活性的化合物，但其不显示抗抑郁活性。采用悬尾试验和强迫游泳试验进行抗抑郁活性筛选，获得抗抑郁活性显著的C21甾体化合物SZJ-1207，并对其抗抑郁药效(经中科院昆明动物所和上海药物研究所等多家单位反复验证)、药代动力学、镇静催眠副作用及急性毒性等进行成药性评价，同时根据化合物的结构对SZJ-1207抗抑郁作用机制进行探索，可能与升高小鼠海马中BDNF有关，但该化合物既不是NMDA NR2B也不是GABA受体激动剂或拮抗剂。该抗抑郁化合物的发现为进一步的新药研究开发奠定基础。