基于5-羟色胺转运蛋白和sigma-1受体的苯基哌嗪烷胺类化合物的设计、合成及抗抑郁活性研究  

Design,synthesis and antidepressant activity evaluation of novel phenylpiperazine alkylamine compounds based on serotonin transporter and sigma-1 receptor

作　　者：汪涛 陈园园 徐祥清[3] 赵松[3] 张桂森[3] 李建其[2] 王冠[2] 

机构地区：[1]复旦大学药学院,上海201203 [2]中国医药工业研究总院上海医药工业研究院化学制药新技术中心,上海201203 [3]江苏恩华药业股份有限公司,江苏徐州221007

出　　处：《中国药物化学杂志》2017年第6期423-433,共11页Chinese Journal of Medicinal Chemistry

基　　金：上海市科学技术委员会科研计划项目(15431902600)

摘　　要：目的以5-羟色胺转运蛋白和sigma-1受体为靶点,设计合成苯基哌嗪烷胺类化合物及其衍生物,研究其体内外生物活性。方法以间氰基苯胺和氰基取代吲哚类化合物为起始原料,经还原胺化、烷基化反应,再与相应的苯基哌嗪类衍生物进行缩合制备系列化合物。经5-羟色胺再摄取抑制实验和sigma-1受体结合实验进行体外活性筛选,采用小鼠强迫游泳实验和小鼠悬尾实验对其中化合物39和42进行体内抗抑郁活性研究。结果与结论共合成36个未见文献报道的新化合物,经质谱和核磁共振氢谱确证结构。体内外药理研究表明:化合物39和42具有较强的5-羟色胺再摄取抑制作用和sigma-1受体高亲和力,Ki值分别为5.77 nmol·L^(-1)/49.95 nmol·L^(-1)和3.48 nmol·L^(-1)/3.30 nmol·L^(-1)。39在两种抑郁模型上均显示出良好的抗抑郁活性,具有作为新型抗抑郁活性分子进行深入研究的价值。In order to discover novel antidepressants with cognitive improvement, we attempted to create novel compounds which have equivalent affinity for SERT and sigma-1 receptor. Thirty-sixphenylpiperazineal- kylamine derivatives were synthesized and examined for activities by binding assays in vitro. The target com- pounds（ 11 - 18,30 - 57 ） were obtained from iodinated intermediates （ 7 - 10,24 - 29 ） condensed with phenylpiperazine derivatives. The structure-activity relationship ssuggested that the group of N-methyl substituent was critical to improve affinity for SERT and sigma-1 receptor and cyano group was necessary to keep affinity for SERT. Compounds 39 and 42 exhibited high affinities for serotonin transporter and sigma-1 receptor,the Ki values were 5.77 nmol·L^-1/49.95nmol·L^-1 and 3.48nmol·L^-1/3.30 nmol·L^-1. In vivo studies, 39 showed significant antidepressant activity in mouse forced swimming and mouse tail test. There- fore, 39 was served as a preferred compound worthy of further study.

关 键 词：5-羟色胺转运蛋白 sigma-1受体 苯基哌嗪烷胺类化合物 抗抑郁活性 

分 类 号：R914[医药卫生—药物化学]