偏向性5-羟色胺2C受体激动剂的设计和研究

Biased agonism has recently become the most important research topic for G protein-coupled receptors (GPCRs). Biased agonists regulate the biological functions of GPCRs more precisely, and could potentially become a new generation of GPCR-targeted drugs. In previous work, we have studied a GPCR——the serotonin 2C (5-HT2C) receptor, and our current project would focus on the same receptor for the design and study of biased agonists. Our research will focus on the following aspects: (1) design and synthesis of both “G protein-biased” and “β-arrestin-biased” 5-HT2C agonists based on the natural product ergotamine; (2) structural biology study of the 5-HT2C receptor using biased agonists, to explore the structural basis for biased agonism; (3) structure-based rational design of 5-HT2C selective biased agonists; (4) evaluation of the pharmacokinetic and toxicity properties of selective compounds, and study of the possibility of 5-HT2C biased agonists as new drugs for schizophrenia using in vivo schizophrenia-like animal models. Expected results from these studies would provide further information on GPCR biased agonism using the 5-HT2C receptor as an example, which could guide the design of biased agonists targeting other GPCRs. Additionally, new anti-schizophrenia drugs with novel mechanism-of-action could potentially be discovered.

偏向性激活是GPCR研究的最新热点。偏向性激动剂能够更加精准地调节GPCR的下游信号通路，有潜力成为靶向GPCR的新一代药物。申请人在前期工作中积累了关于5-HT2C受体的研究经验，本项目将继续选取该受体为研究目标，进行偏向性激动剂的设计和研究：①通过对天然产物麦角胺的结构改造获取G蛋白-偏向和β-arrestin-偏向的5-HT2C受体激动剂；②以偏向性激动剂为工具进行5-HT2C受体的结构生物学研究，揭示其偏向性激活的结构基础；③通过基于结构的合理药物设计提高偏向性激动剂的选择性，获得对5-HT2C具有高选择性的化合物；④对高选择性化合物进行代谢性质、安全性，以及体内抗精神分裂症活性的评价，以考察其作为新型抗精神分裂症药物的潜力。预期的研究成果将为以5-HT2C受体为代表的GPCR的偏向性激活提供信息，为类似偏向性激动剂的设计提供指导，并有望获得具有全新作用机制的抗精神分裂症候选药物。