具认知改善作用的多靶点抗精神分裂活性分子设计合成及活性研究

All of the commercially available antipsychotic drugs have nearly no effect on improving cognitive impairment in schizophrenics currently, which is difficult to meet the clinical needs. Studies have shown that cognitive function could be agumented by dopamine D3 receptor antagonists and led to more and more attention paid by many pharmaceutical companies world wide. However, there is a great challenge for designing D3R prefering, D3R/D2R dual antagonist derivertives with high potency and specificity because of the high degree of sequence identity between D2R and D3R as well as less distribution and low density of D3R in human brain. In our continuing efforts on antipsychoric agents research, a representitive compound SIPI6390 was designed and synthesized, which demonstrated subnanomolar concentration affinity for D3R/D2R with good specificity on pharmacology assays. Interestingly, further study revealed that compound SIPI6390 also displayed high affinity for both 5-HT1AR and 5-HT2AR, in accordance with the characteristics of multi-target antipsychotic drugs currently in clinical trials, suggesting that it is a good starting point for further structural optimization. On the basis of our previous results, a series of SIPI6390-like derivatives, with similar receptor binding feature, will be designed, synthesized and structurally optimized by the means of computer-aided drug design. Moreover, all of the new compounds will be screened in vitro receptor binding assays, then the preferred ones will be tested in anmimal models of schizophrenia. This work will lay a good foundation for developing novel SIPI6390 analogs with broad-spectrum, high efficacy and improved cognitive function, and provide a theoratical and practical research guide for development of new multi-target antipsychotic drugs.

目前市售抗精神分裂药对认知障碍几无改善，难以满足临床。研究表明，拮抗多巴胺D3受体可改善认知症状，已成为抗精神分裂新药研发重点。然D3、D2受体同源性高，D3较D2分布窄、密度低，故设计高效选择性D3/D2受体拮抗剂为该类药物研发难点与关键。本课题组前期针对D3/D2受体拮抗剂研究，发现SIPI6390等化合物对D3/D2具高亲和力（亚纳摩尔级）及良好选择性，对5-HT1A/5-HT2A亦具强亲和力，与目前临床在研新型多靶点抗精神分裂药受体结合特征一致，极具深入研究价值。本项目基于上述发现，以SIPI6390为先导结构，结合计算机辅助药物设计，在保留D3/D2受体亲和力和选择性，兼具5-HT1A/5-HT2A受体亲和力的基础上，进行化合物结构优化设计和体内外活性筛选，为指导发现广谱、高效、可改善认知功能的SIPI6390类活性分子奠定基础，亦为多靶点抗精神分裂新药研发提供理论和实践的借鉴。

本项目进行SIPI6390等环己基胺类新型选择性D2/D3受体拮抗剂的设计合成、体外D2/D3/5-HT1A/5-HT2A受体亲和力测定、体内抗精神分裂活性及初步安全性研究，并结合计算机辅助药物设计，探索影响配体对D2/D3受体亚型选择性大小的关键药氨基酸和效团、影响5-HT1A/5-HT2A受体亲和力的关键芳基基团，并发现具认知功能改善作用及开发价值的多靶点抗精神分裂活性分子结构。.通过本项目的研究共设计合成43个SIPI6390类新化合物。结合计算机辅助药物设计及基本构效关系分析，发现Asp77 (D2)、Asp110 (D3)为影响D2/D3受体亚型选择性大小的关键氨基酸，配体分子存在多个碱性中心干扰配体/D3受体的识别。同时，配体的芳基脲、氨基甲酸酯、芳基甲酰基、反式构型环己基结构为提高D2、D3亲和力及D2/D3亚型选择性的优势片段，苯并异噻唑基为调节5-HT1A/5-HT2A受体亲和力的重要芳基基团。经体内多个药效模型评价、作用机制研究、体内药代特性及毒副作用考察，发现具显著认知功能改善作用及开发价值的抗精神分裂活性分子SIPI6398。.通过本课题的研究，发表3篇SCI研究论文，并申请6项国内外发明专利，1项中国发明专利获得授权。本项目的研究结果可为定向设计合成具认知功能改善作用的新型多靶点抗精神分裂症活性分子提供指导依据。