Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Bioorg Med Chem. 2012 Feb 15;20(4):1545-56. doi: 10.1016/j.bmc.2011.12.039. Epub 2012 Jan 4.
Two series of arylpiperazinyl-alkyl quinoline-, isoquinoline-, naphthalene-sulfonamides with flexible (13-26) and semi-rigid (33-36) alkylene spacer were synthesized and evaluated for 5-HT(1A), 5-HT(2A), 5-HT(6), 5-HT(7) and selected compounds for D(2), D(3), D(4) receptors. The compounds with a mixed 5-HT and D receptors profile 16 (N-{4-[4-(3-chlorophenyl)-piperazin-1-yl]-butyl}-3-quinolinesulfonamide) and 36 (4-(4-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethyl}-piperidine-1-sulfonyl)-isoquinoline), displaying antagonistic activity at 5-HT(7), 5-HT(2A), D(2) postsynaptic sites, produced antidepressant-like effects in the forced swim test in mice and showed significant anxiolytic activity in the plus-maze test in rats. The lead compound 36, a multi-receptor 5-HT(2A)/5-HT(7)/D(2)/D(3)/D(4) agent, also displayed significant antipsychotic properties in the MK-801-induced hyperlocomotor activity in mice.
合成了两个系列的芳基哌嗪基-烷基喹啉、异喹啉、萘磺酰胺，其中包含柔性（13-26）和半刚性（33-36）亚乙基间隔基，并对其进行了 5-HT(1A)、5-HT(2A)、5-HT(6)、5-HT(7)和部分化合物的 D(2)、D(3)、D(4)受体评估。具有混合 5-HT 和 D 受体特性的化合物 16（N-{4-[4-(3-氯苯基)-哌嗪-1-基]-丁基}-3-喹啉磺酰胺）和 36（4-(4-{2-[4-(4-氯-苯基)-哌嗪-1-基]-乙基}-哌啶-1-磺酰基)-异喹啉），对 5-HT(7)、5-HT(2A)、D(2)突触后部位具有拮抗活性，在小鼠强迫游泳试验中产生抗抑郁样作用，并在大鼠加迷宫试验中表现出显著的抗焦虑活性。先导化合物 36 是一种多受体 5-HT(2A)/5-HT(7)/D(2)/D(3)/D(4)药物，在 MK-801 诱导的小鼠过度活跃活动中也表现出显著的抗精神病特性。
