Synthesis of 3,4-dihydroquinolin-2(1H)-one derivatives with anticonvulsant activity and their binding to the GABAA receptor

Abstract

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 (ED₅₀). In vitro binding experiments with the GABA_A 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, ED₅₀ = 10.1 mg/kg; scPTZ, ED₅₀ = 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_A receptors (IC₅₀ = 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_A receptor. Compound 5b showed significant interactions with residues at the benzodiazepines binding site on the GABA_A receptor. The physicochemical and pharmacokinetic properties of the target compounds were predicted using Discovery Studio 2019 and ChemBioDraw Ultra 14.0.

Keywords: Anticonvulsant; GABA(A) receptor; MES; Molecular docking studies; Synthesis.