State Key Laboratory of Virology, Ministry of Education Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Science, Luojiashan Road, Wuhan 430071, China.
Eur J Med Chem. 2012 Feb;48:338-46. doi: 10.1016/j.ejmech.2011.12.037. Epub 2011 Dec 29.
In the present study on the development of new anticonvulsants, 16 new1-(8-(benzyloxy)quinolin-2-yl-6-substituted-4,6-diazaspiro[2,4]heptane-5,7-diones were synthesized and tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous 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. Two compounds 8e and 8j showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 8e showed the MES-induced seizures with ED(50) value of 8.6 mg/kg and TD(50) value of 365.3 mg/kg after intraperitoneally injection to mice, which provided compound 8e with a protective index (TD(50)/ED(50)) of 26.8 in the MES test.
在本项关于新型抗惊厥药物开发的研究中，合成了 16 种新型的 1-(8-(苄氧基)喹啉-2-基-6-取代-4,6-二氮杂螺[2,4]庚烷-5,7-二酮，并采用最大电休克（MES）和皮下戊四唑（scPTZ）筛选法对其抗惊厥活性进行了测试。这两种方法是用于早期鉴定候选抗惊厥药物的最广泛使用的惊厥模型。通过转棒试验确定了它们的神经毒性。在用于抗惊厥评估的两种模型中，两种化合物 8e 和 8j 均表现出有希望的抗惊厥活性。最活跃的化合物 8e 在腹腔注射到小鼠后，其 MES 诱导的癫痫发作的 ED（50）值为 8.6mg/kg，TD（50）值为 365.3mg/kg，在 MES 测试中，化合物 8e 的保护指数（TD（50）/ED（50））为 26.8。
