College of Pharmacy, Yanbian University, No. 1829, JuZi Street, Yanji, Jilin 133000, China.
Eur J Med Chem. 2010 Jul;45(7):3080-6. doi: 10.1016/j.ejmech.2010.03.041. Epub 2010 Apr 3.
A series of novel 10-alkoxy-5, 6-dihydro-triazolo[4,3-d]benzo[f][1,4]oxazepine derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). In the MES test, compound 10-Heptyloxy-5, 6-dihydro-triazolo[4,3-d]benzo[f][1,4]oxazepine (8f) was found to possess better anticonvulsant activity and higher safety than marketed drugs carbamazepine and phenytoin with an ED(50) value of 6.9 mg/kg a PI value of 9.5. To explain the possible mechanism of anticonvulsant activity, compound 8f was tested in pentylenetetrazole, isoniazid, thiosemicarbazide, 3-mercaptopropionic acid and Bicuculline induced seizures tests. The results suggest that compound 8f exerts anticonvulsant activity through GABA-mediated mechanism.
一系列新型 10-烷氧基-5,6-二氢-三唑并[4,3-d]苯并[f][1,4]恶嗪衍生物被合成，并通过最大电休克（MES）试验筛选其抗惊厥活性，其神经毒性通过旋转棒神经毒性试验（Tox）进行评估。在 MES 试验中，发现化合物 10-庚氧基-5,6-二氢-三唑并[4,3-d]苯并[f][1,4]恶嗪（8f）具有比市售药物卡马西平和苯妥英钠更好的抗惊厥活性和更高的安全性，ED（50）值为 6.9mg/kg，PI 值为 9.5。为了解释抗惊厥活性的可能机制，对化合物 8f 进行了戊四氮、异烟肼、硫代卡巴肼、3-巯基丙酸和印防己毒素诱导的惊厥试验。结果表明，化合物 8f 通过 GABA 介导的机制发挥抗惊厥活性。
