Song Mingxia, Zhao Wennan, Zhu Yangnv, Liu Wenli, Deng Xianqing, Huang Yushan
Medical College, Jinggangshan University, Ji'an, China.
Ji'an Key Laboratory of Personalized Drug Research of Neuropsychiatric Diseases, Ji'an, China.
Front Chem. 2022 Jun 23;10:925281. doi: 10.3389/fchem.2022.925281. eCollection 2022.
Epilepsy, a severe brain disease affecting a large population, is treated mainly by antiepileptic drugs (AEDs). However, toxicity, intolerance, and low efficiency of the available AEDs have prompted the continual attempts in the discovery of new AEDs. In this study, we discovered a skeleton of triazolopyrimidine for the development of new AEDs. The design, synthesis, anticonvulsant activity evaluation of triazolopyrimidines and , and pyrazolopyrimidines are reported. We found that most triazolopyrimidines showed anticonvulsive activity in the maximal electroshock (MES) and pentetrazol (PTZ)-induced seizure models. On the contrary, pyrazolopyrimidines showed weak or no protective effects. Among the tested derivatives, compound , holding a median effective dose (ED of 15.8 and 14.1 mg/kg against MES and PTZ-induced seizures, respectively, was found to be the most potent one. Moreover, the protection index (PI) value of was significantly higher than that of the available AEDs such as valproate, carbamazepine, and diazepam. The antiepileptic efficacy of compound was also observed in the 3-mercaptopropionic acid and bicuculline-induced seizure models. Antagonistic effects of flumazenil and 3-MP for the anticonvulsive activity of and also the radioligand-binding assay confirmed the involvement of GABA receptors, at least benzodiazepine (BZD) receptor, in the anticonvulsant activity of compound . The docking study of compounds and with GABA receptor confirmed and explained their affinity to the BZD receptors.
癫痫是一种影响大量人群的严重脑部疾病，主要通过抗癫痫药物（AEDs）进行治疗。然而，现有AEDs的毒性、耐受性和低效性促使人们不断尝试发现新的AEDs。在本研究中，我们发现了一种用于开发新型AEDs的三唑并嘧啶骨架。本文报道了三唑并嘧啶和吡唑并嘧啶的设计、合成及其抗惊厥活性评价。我们发现，大多数三唑并嘧啶在最大电休克（MES）和戊四氮（PTZ）诱导的癫痫模型中表现出抗惊厥活性。相反，吡唑并嘧啶表现出较弱的保护作用或无保护作用。在测试的衍生物中，化合物对MES和PTZ诱导的癫痫发作的半数有效剂量（ED）分别为15.8和14.1mg/kg，被发现是最有效的一种。此外，化合物的保护指数（PI）值显著高于丙戊酸盐、卡马西平和地西泮等现有AEDs。在3-巯基丙酸和荷包牡丹碱诱导的癫痫模型中也观察到了化合物的抗癫痫疗效。氟马西尼和3-MP对化合物抗惊厥活性的拮抗作用以及放射性配体结合试验证实，至少苯二氮䓬（BZD）受体参与了化合物的抗惊厥活性。化合物和与GABA受体的对接研究证实并解释了它们对BZD受体的亲和力。
