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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,K1值分别为5.77 nmol·L-1/49.95 nmol· L-和3.48 nmol·L-1/3.30 nmol·L-.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-sixphenylpiperazinealkylamine derivatives were synthesized and examined for activities by binding assays in vitro.The target compounds(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-1/49.95 nmol·L-1 and 3.48 nmol·L-1/3.30 nmol·L-1.In vivo studies,39 showed significant antidepressant activity in mouse forced swimming and mouse tail test.Therefore,39 was served as a preferred compound worthy of further study.