Kamiński Krzysztof, Obniska Jolanta
Department of Medicinal Chemistry, Jagiellonian University, Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Bioorg Med Chem. 2008 May 1;16(9):4921-31. doi: 10.1016/j.bmc.2008.03.037. Epub 2008 Mar 17.
In the present study on the development of new anticonvulsants, the library of differently substituted N-phenylamino pyrrolidine-2,5-dione and hexahydro-isoindole-1,3-dione derivatives was synthesized. The anticonvulsant activity of all the compounds was evaluated using the maximal electroshock (MES) and pentylenetetrazole (scPTZ) screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. The pharmacological results revealed that the majority of compounds were effective in electrical (MES) and/or pentylenetetrazole induced seizure (scPTZ) models. The quantitative in vivo anticonvulsant evaluation of N-phenylamino-3,3-dimethyl-pyrrolidine-2,5-dione (15), conducted at the time of peak pharmacodynamic activity (TPE), showed the MES ED(50) value of 69.89mg/kg in rats. The median toxic dose (TD(50)) was 500mg/kg, providing compound 15 with a protective index (TD(50)/ED(50)) of 7.15 in the MES test.
在当前关于新型抗惊厥药物开发的研究中，合成了不同取代的N - 苯基氨基吡咯烷 - 2,5 - 二酮和六氢异吲哚 - 1,3 - 二酮衍生物库。使用最大电休克（MES）和戊四氮（scPTZ）筛选试验评估了所有化合物的抗惊厥活性，这两种试验是早期鉴定候选抗惊厥药物时应用最广泛的癫痫发作模型。通过转棒试验测定了它们的神经毒性。药理学结果表明，大多数化合物在电休克（MES）和/或戊四氮诱导的癫痫发作（scPTZ）模型中有效。在药效学活性峰值（TPE）时对N - 苯基氨基 - 3,3 - 二甲基 - 吡咯烷 - 2,5 - 二酮（15）进行的体内定量抗惊厥评估显示，大鼠的MES ED(50)值为69.89mg/kg。半数中毒剂量（TD(50)）为500mg/kg，在MES试验中化合物15的保护指数（TD(50)/ED(50)）为7.15。
