精神分裂症是一种严重的精神疾病，临床表现以阳性、阴性症状以及认知功能障碍为主。针对阳性症状目前有药物可得到部分控制，但针对阴性症状和认知障碍至今仍是一个没有解决的难题。alpha-7尼古丁乙酰胆碱受体是大脑胆碱神经系统的一个重要受体，其激动剂是改善精神分裂疾病患者认知障碍的潜在药物。本项目拟通过对alpha-7受体-激动剂的作用模式分析，并结合计算机辅助虚拟筛选进行新激动剂分子设计；化学合成新分子；通过同位素标记受体亲和实验、膜片钳电生理学研究以及动物模型评价等方法，在不同层次研究所合成化合物的生物学性质、受体选择性及分子机制等。本项目将综合药物设计、合成及生物活性评价策略，深入解析alpha-7受体-激动剂的作用模式，发展相关化合物的合成方法，建立稳定可靠的精神分裂症药物评价体系，阐明作用机制，解析构效关系，并获得安全、高效的靶向alpha-7受体的抗精神分裂症药物先导结构。

Schizophrenia is characterized by positive and negative symptoms and cognitive impairment. While positive symptoms are partially managed with current medications, cognitive deficits and negative symptoms still remain an unmet medical need. Alpha-7 nicotinic acetylcholine receptor (nAChR) is an important part of the cholinergic nerve system in the brain. Agonists of alpha-7 nAChR are considered as the potential medicines for treatment of cognitive dysfunctions of Schizophrenia. In this project, novel alpha-7 nAChR agonists will be designed based on the analysis of the binding mode of alpha-7 nAChR and known agonist and combined with computer-aided virtual screening. Chemical syntheses will be performed to get the designed molecules. The biological behaviors, receptor selectivity, and molecular mechanism of the obtained compounds will be investigated in different levels, which including isotope labeled receptor affinity analysis, physiological studies using patch clamp, and treatment on the animal model of Schizophrenia, etc. This projects will integrate the strategies of drug design, chemical synthesis, and biological investigation to study the interaction of receptor-agonist, develop the methodology of chemical synthesis, setup a reliable and stable platform for evaluating anti-Schizophrenia agents, clarify the molecular mechanism and structure-activity relationship. A couple of alpha-7 nAChR-targeted novel anti-Schizophrenia lead compounds will be developed through the implementation of this project.