Synthesis of 1,3,4-oxadiazole derivatives with anticonvulsant activity and their binding to the GABAA receptor
Synthesis of 1,3,4-oxadiazole derivatives with anticonvulsant activity and their binding to the GABAA receptor
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具有抗惊厥活性的1,3,4-恶二唑衍生物的合成及其与GABAA受体的结合
DOI：
10.1016/j.ejmech.2020.112672
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发表时间：
2020-11-15
影响因子：
6.7
通讯作者：
Quan, Zheshan
中科院分区：
文献类型：
--
作者：
Wang, Shiben;Liu, Hui;Quan, Zheshan
本研究采用最大电击（MES）和皮下戊四唑（scPTZ）模型，设计并合成了一系列1,3,4-恶二唑衍生物（5a-s， 10a-s和16a-d），以测试目标化合物的体内抗惊厥活性。采用旋转杆法测定目标化合物的神经毒性（NT）。选取7种具有潜在活性的化合物分别进行50%有效剂量（ED50）和50%毒性剂量（TD50）试验。药理实验结果显示，6-（（5-（戊硫代）-1,3,4-恶二唑-2-基）甲氧基）-3,4-二氢喹啉-2(1H)- 1 （5b）的抗惊厥活性最佳（MES, ED50 = 8.9 mg/kg; scPTZ, ED50 = 10.2 mg/kg），其抗惊厥活性大于卡马西平和乙氧亚胺。在体外结合实验中，化合物5b对GABA(A)受体的结合亲和力最强（IC50 = 0.11 μ M）。化合物5b在低剂量（1 mg/kg）下表现出显著的抗焦虑活性。对大鼠脑内GABA含量进行了研究，结果表明化合物5b可能对GABA系统有影响。在我们的分子对接实验中，化合物5b与GABA(A)受体上苯二氮卓结合位点的残基表现出显著的相互作用。使用Discovery Studio 2019和ChemBioDraw Ultra 14.0预测目标化合物的结构、物理化学和药代动力学性质。最后证明化合物5b主要作用于GABA(A)受体。因此，本研究为进一步研究癫痫提供了潜在的候选药物。(C) 2020 Elsevier Masson SAS。版权所有。
In this study, a series of 1,3,4-oxadiazole derivatives (5a-s, 10a-s, and 16a-d) were designed and synthesized using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) models, to test the anticonvulsant activity of the target compounds in vivo. The neurotoxicity (NT) of the target compounds was measured using the rotating rod (ROT) method. Seven compounds with potential activity were selected to test the 50% effective dose (ED50) and 50% toxic dose (TD50). Pharmacological experiments revealed that 6-((5-(pentylthio)-1,3,4-oxadiazol-2-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (5b) showed the best anticonvulsant activity (MES, ED50 = 8.9 mg/kg; scPTZ, ED50 = 10.2 mg/kg), which was greater than the activities of carbamazepine and ethosuximide. Compound 5b exhibited the most potent binding affinity toward the GABA(A) receptor (IC50 = 0.11 mu M) in the in vitro binding experiments. Compound 5b displayed significant anxiolytic activity at a low dose (1 mg/kg) in the elevated plus maze (EPM) test. The GABA content in rat brains was also investigated, and the results showed that compound 5b might have affected the GABA system. In our molecular docking experiment, compound 5b showed significant interactions with residues present at the benzodiazepine binding site on the GABA(A) receptor. The structure and physicochemical and pharmacokinetic properties of the target compound were predicted using Discovery Studio 2019 and ChemBioDraw Ultra 14.0. Finally we demonstrated that compound 5b mainly acted on GABA(A) receptor. Thus the present study has provided potential candidates for further investigation in epilepsy. (C) 2020 Elsevier Masson SAS. All rights reserved.