Zheng Y, Wang S-B, Cao X, Liu D-C, Shu B, Quan Z-S
College of Pharmacy, Yanbian University, Jilin, China.
Drug Res (Stuttg). 2014 Jan;64(1):40-6. doi: 10.1055/s-0033-1351316. Epub 2013 Aug 21.
A series of novel 4-(4-substitutedphenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock test (MES) and their neurotoxicity was evaluated by the rotarod neurotoxicity test (TOX). In the MES test, compound 4-{4-[(3-fluorobenzyl)oxy]phenyl}-3-methyl-1H-1,2,4-triazol-5(4H)-one (4n) was found to possess better anticonvulsant activity and higher safety than marketed drugs Carbamazepine with an ED50 value of 25.5 mg/kg and protective index (PI) value>48.8. In addition, the potency of compound 4n against seizures induced by Pentylenetetrazole, 3-Mercaptopropionic acid, and Bicuculline suggested its broad spectrum activity, and the mechanisms of action including inhibition of voltage-gated ion channels and modulation of GABAergic activity might involve in its anticonvulsant activity.
合成了一系列新型的4-(4-取代苯基)-3-甲基-1H-1,2,4-三唑-5(4H)-酮衍生物，并通过最大电休克试验（MES）筛选其抗惊厥活性，通过转棒神经毒性试验（TOX）评估其神经毒性。在MES试验中，发现化合物4-{4-[(3-氟苄基)氧基]苯基}-3-甲基-1H-1,2,4-三唑-5(4H)-酮（4n）具有比市售药物卡马西平更好的抗惊厥活性和更高的安全性，其半数有效剂量（ED50）值为25.5mg/kg，保护指数（PI）值>48.8。此外，化合物4n对戊四氮、3-巯基丙酸和荷包牡丹碱诱导的癫痫发作的效力表明其具有广谱活性，其作用机制包括抑制电压门控离子通道和调节GABA能活性，可能涉及其抗惊厥活性。
