Synthesis of 1,3,4-oxadiazole derivatives with anticonvulsant activity and their binding to the GABA
| Autor: | Jun Li, Guangyong Li, Kang Lei, Hui Liu, Shiben Wang, Ren-Min Liu, Xuekun Wang, Zhe-Shan Quan |
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| Rok vydání: | 2020 |
| Předmět: |
Elevated plus maze
medicine.drug_class medicine.medical_treatment Chemistry Techniques Synthetic Pharmacology 01 natural sciences Anxiolytic 03 medical and health sciences Drug Discovery medicine Animals 030304 developmental biology 0303 health sciences Oxadiazoles 010405 organic chemistry Chemistry GABAA receptor Organic Chemistry Brain General Medicine Carbamazepine Receptors GABA-A Effective dose (pharmacology) 0104 chemical sciences Rats Ethosuximide Anticonvulsant Drug Design Anticonvulsants Discovery Studio medicine.drug Protein Binding |
| Zdroj: | European journal of medicinal chemistry. 206 |
| ISSN: | 1768-3254 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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