In this work we describe the synthesis, docking studies and biological evaluation of a focused library of novel arylpiperazinyl derivatives of 8-acetyl-7-hydroxy-4-methylcoumarin. The new compounds were screened for their 5-HT_1A and 5-HT_2A receptor affinity. Among the evaluated compounds, six displayed high affinities to 5-HT_1A receptors (4a-0.9 nM, 6a-0.5 nM, 10a-0.6 nM, 3b-0.9 nM, 6b-1.5 nM, 10b-1 nM). Compound 6a and 10a bearing a bromo- or methoxy- substituent in ortho position of the piperazine phenyl ring, were identified as potent antagonists of the 5-HT_1A receptors. In the tail suspension test, mice injected with 6a showed a dose-dependent increase in depressive-like behavior that was related to a decrease in locomotor activity. Compound 10a did not decrease or prolong immobility time nor did it affect home cage activity. Molecular docking studies using 5-HT_1A and 5-HT_2A homology models revealed structural basis of the high affinity of ortho-substituted derivatives and subtle changes in amino acid interactions patterns depending on the length of the alkyl linker.

在这项工作中，我们描述了8-乙酰基-7-羟基-4-甲基香豆素的新型芳基哌嗪基衍生物的文库的合成，对接研究和生物学评估。筛选新化合物的5-HT _1A和5-HT _2A受体亲和力。在所评估的化合物中，六种化合物显示出对5-HT _1A受体的高亲和力（4a -0.9 nM，6a- 0.5 nM，10a -0.6 nM，3b -0.9 nM，6b -1.5 nM，10b -1 nM）。在邻位带有溴或甲氧基取代基的化合物6a和10a哌嗪苯环的位置被确定为5-HT _1A受体的有效拮抗剂。在尾部悬吊测试中，注射6a的小鼠表现出与运动活动性下降有关的抑郁样行为的剂量依赖性增加。化合物10a不会减少或延长不动时间，也不会影响笼子的活动。使用5-HT _1A和5-HT _2A同源性模型进行的分子对接研究揭示了邻位取代衍生物的高亲和力以及氨基酸相互作用模式的细微变化（取决于烷基接头的长度）的结构基础。