Abstract:
: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 GABAA receptor (IC50 = 0.11 μM) 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 GABAA 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 GABAA receptor. Thus the present study has provided potential candidates for further investigation in epilepsy.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Wang S,Liu H,Wang X,Lei K,Li G,Li J,Liu R,Quan Zdoi
10.1016/j.ejmech.2020.112672subject
Has Abstractpub_date
2020-11-15 00:00:00pages
112672eissn
0223-5234issn
1768-3254pii
S0223-5234(20)30644-9journal_volume
206pub_type
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