Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University, Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Bioorg Med Chem Lett. 2011 Oct 1;21(19):5800-3. doi: 10.1016/j.bmcl.2011.07.118. Epub 2011 Aug 6.
Twenty-two new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones were synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens in mice. Several compounds were tested additionally in the 6-Hz psychomotor seizure model. The neurotoxicity was determined applying the rotarod test. Excluding one compound, all other molecules were found to be effective in at least one seizure model. The most active were 1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (14), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3-methylpyrrolidine-2,5-dione (17), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3,3-dimethylpyrrolidine-2,5-dione (23) and 3,3-dimethyl-1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (26). These compounds showed high activity in the 6-Hz psychomotor seizure test as well as were active in the maximal electroshock and subcutaneous pentylenetetrazole (14 and 23) screens. Initial SAR studies for anticonvulsant activity have been discussed.
合成了 22 种新的 1-[2-氧代-2-(4-苯基哌嗪-1-基)乙基]吡咯烷-2,5-二酮，并测试了它们的抗惊厥活性。最初的抗惊厥筛选是在小鼠中使用标准的最大电休克（MES）和皮下戊四氮（scPTZ）筛选进行的。在 6-Hz 运动性惊厥模型中还测试了几种化合物。神经毒性通过旋转棒试验确定。除了一种化合物外，所有其他分子在至少一种惊厥模型中都被证明是有效的。最活跃的是 1-(2-氧代-2-{4-[3-(三氟甲基)苯基]哌嗪-1-基}乙基)吡咯烷-2,5-二酮（14）、1-{2-[4-(4-氯苯基)哌嗪-1-基]-2-氧代乙基}-3-甲基吡咯烷-2,5-二酮（17）、1-{2-[4-(4-氯苯基)哌嗪-1-基]-2-氧代乙基}-3,3-二甲基吡咯烷-2,5-二酮（23）和 3,3-二甲基-1-(2-氧代-2-{4-[3-(三氟甲基)苯基]哌嗪-1-基}乙基)吡咯烷-2,5-二酮（26）。这些化合物在 6-Hz 运动性惊厥试验中表现出高活性，并且在最大电休克和皮下戊四氮（14 和 23）筛选中也具有活性。讨论了抗惊厥活性的初始 SAR 研究。
