吡咯烷酮-2类化合物的设计、合成及快速起效抗抑郁活性评价

Depression especially major depressive disorder (MDD) is a mental disorder characterized by prominent and persistent low mood, mental retardation, cognitive impairment, volitional decline and somatic symptoms. Unitl now, the pathogenesis of depression has not yet been clarified. Although antidepressants have been used in clinics for several decades, most of them were inadequate in efficiency and had many serious side effects. Developing new antidepressants with rapid onset and lower side effects are desirable. The N-methyl-D-aspartate receptors (NMDARs), a part of the ionotropic glutamate receptor family, are the most important targets for the rapid onset of antidepressant effect. According to our previous work, antidepressant Fenkelutone, WJ and their derivatives could modulate the expression of glutamate NMDA receptor protein, and also had a very good protective effect on NMDA induced neurotoxicity in PC12 cells. In this project, a series of novel antidepressant multisubstituted pyrrolidin-2-ones based on structural skeletons of Fenkelutone and WJ are designed and synthesized. Evaluation of the target compounds on the activty of modulating NMDARs, the structure-activity relationship and the molecular mechanism is carried out together with determining the effectiveness of rapid onset antidepressant in vivo. Our aim is to find a new type of rapid-onset antidepressant molecules and provide scientific evidences for the development of antidepressant drugs of pyrroliones.

抑郁症特别是重度抑郁症是以显著而持久的心境低落、认知功能损害、意志活动减退等症状的一类心境障碍。抑郁症发病机制至今尚未完全阐明。目前临床用抗抑郁药物大多存在起效慢、有效率低、服用周期长、不良反应大等不足。快速起效、毒副作用低的抗抑郁药物研究是当前研究热点。离子型谷氨酸受体亚型N-甲基-D-天门冬氨酸（NMDA）受体是快速起效抗抑郁作用重要靶点之一。前期研究发现，抗抑郁活性吡咯烷酮-2结构化合物芬克罗酮（Fenkelutone）、吡咯并异喹啉化合物（WJ）及其衍生物可调控谷氨酸NMDA受体蛋白表达，并且对NMDA诱导PC12细胞损伤有非常好的保护作用。本项目以活性先导物芬克罗酮和WJ为结构基础，设计、合成多取代吡咯烷酮-2类化合物，筛选靶向调控谷氨酸NMDA受体的活性化合物，阐明其构效关系和分子作用机制，在体内研究确定其快速起效抗抑郁的有效性，为吡咯烷酮-2类抗抑郁症药物的研制提供科学依据。

抑郁症是严重危害人类的疾病，现有抗抑郁药大多存在起效慢、疗效低等不足。寻找速效、选择性好的抗抑郁分子已成为当前研究重要方向。研究表明，拮抗NMDAR、激活AMPAR及mTOR等下游信号通路可能是快速起效抗抑郁的机制。我们设计、合成了102个吡咯烷酮-2类衍生物，建立了NMDA诱导的PC12细胞损伤模型开展了所用目标化合物对NMDA诱导的PC12细胞损伤保护活性研究，并开展了高活性化合物Ca2+拮抗活性评价。研究表明，化合物C12、C22、F13和F26具有显著的保护活性，细胞内Ca2+显著被抑制，并获得了该类型化合物的构效关系。我们克级制备了化合物C12和F13，通过体内小鼠抑郁实验确定了其抗抑郁的有效性。作用机制研究表明，该类化合物作用靶点为NMDA受体甘氨酸位点，是该位点的拮抗剂。发表了SCI收录论文7篇，核心期刊1篇，申请国家发明专利3件，其中授权1件。本项目为新型抗抑郁药的研制奠定基础。