College of Pharmacy, Liaocheng University, Liaocheng, Shandong 252059, China.
College of Life Sciences, Liaocheng University, Liaocheng, Shandong 252059, China.
Bioorg Chem. 2020 Oct;103:104182. doi: 10.1016/j.bioorg.2020.104182. Epub 2020 Aug 27.
In this study, a series of 3,4-dihydroquinolin-2(1H)-one derivatives were designed and synthesized using two experimental models, namely maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), to test the anticonvulsant activity of the target compound in vivo (i.p. in Kunming mice). The neurotoxicity (NT) of the target compound was measured by the rotating rod method (i.p. in Kunming mice). Six compounds with potential activity were selected from the two experimental models to test the 50% effective dose (ED). In vitro binding experiments with the GABA receptor were also performed. The results of the pharmacological experiments showed that compound 7-((5-(pentylthio)-1,3,4-oxadiazol-2-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (5b) showed the best anticonvulsant activity (MES, ED = 10.1 mg/kg; scPTZ, ED = 9.3 mg/kg), which was superior to activities shown by carbamazepine and ethosuximide, and it also exhibited the most potent binding affinity to GABA receptors (IC = 0.12 μM). The GABA content in Wistar rat brains (i.p.) was also investigated, and the results showed that compound 5b may have a certain effect on the GABA system, as it increased the GABA concentration in the brain of rats. Molecular docking was used to study the binding mode of compound 5b and the GABA receptor. Compound 5b showed significant interactions with residues at the benzodiazepines binding site on the GABA receptor. The physicochemical and pharmacokinetic properties of the target compounds were predicted using Discovery Studio 2019 and ChemBioDraw Ultra 14.0.
在这项研究中，使用两种实验模型（最大电休克（MES）和皮下戊四氮（scPTZ））设计和合成了一系列 3,4-二氢喹啉-2(1H)-酮衍生物，以测试目标化合物在体内（昆明小鼠腹腔注射）的抗惊厥活性。目标化合物的神经毒性（NT）通过旋转棒法（昆明小鼠腹腔注射）测量。从两个实验模型中选择了 6 种具有潜在活性的化合物来测试 50%有效剂量（ED）。还进行了与 GABA 受体的体外结合实验。药理实验结果表明，化合物 7-((5-(戊基硫基)-1,3,4-恶二唑-2-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮（5b）表现出最好的抗惊厥活性（MES，ED = 10.1 mg/kg；scPTZ，ED = 9.3 mg/kg），优于卡马西平和乙琥胺的活性，并且对 GABA 受体也表现出最强的结合亲和力（IC = 0.12 μM）。还研究了 Wistar 大鼠脑（腹腔注射）中的 GABA 含量，结果表明化合物 5b 可能对 GABA 系统有一定的影响，因为它增加了大鼠脑中的 GABA 浓度。使用分子对接研究了化合物 5b 和 GABA 受体的结合模式。化合物 5b 与 GABA 受体苯二氮䓬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 预测了目标化合物的物理化学和药代动力学性质。
