新型5-HT重摄取抑制剂的设计、合成及活性评价

在对已知各种结构类型的5-HT重摄取抑制剂分子结构全面分析的基础上, 建立了SSRIs药效团模型. 基于该模型应用UNITY程序对NCI-3D和Maybridge-3D数据库进行三维结构的限制性查询, 在获得的命中结构的信息指导下, 设计合成了3种全新结构类型的化合物, 并完成了初步的药理活性评价. 这些化合物均显示出不同程度的5-HT重摄取抑制活性, 其中5个化合物显示高抑制活性. 哌嗪取代的二苯脒类化合物的结构新颖, 较好地符合5-HT重摄取抑制剂药效团模型, 与SSRIs类化合物三维定量构效关系研究得到的CoMFA模型有较好的适配性.

Design, Synthesis and Activity Evaluation of Novel Selective Serotonin Reuptake Inhibitors

Depression is a kind of common and severe mental illness. During the past two decades, selective serotonin reuptake inhibitors(SSRIs) have been proved to be a safer and more effective resistance than the first-generation antidepressants(TCAs and MAOIs), and have gained incredible popularity.Based on the conformation analysis and pharmacophore information of SSRIs, flexible database searching from the NCI-3D and Maybridge-3D database was performed. Three classes of the new compounds structures were designed and 27 analogues were prepared and evaluated as potential antidepressant agents. Biphenylbenzamidine derivative Ⅰ-19 showed good activity of affinity to the 5-HT transporter. It can be used as the lead structure for drug design with the objective of making more potent inhibitors against 5-HT transporter.