Design, synthesis and pharmacological evaluation of triazolopyrimidines derivatives as novel agonists for benzodiazepine receptor

In this paper, two series of triazolopyrimidines derivatives were designed, synthesized, and all the target compounds were structurally confirmed using 1H NMR, 13C NMR and HRMS methods. Pharmacological experiments were carried out using maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and rotating rod (ROT) models for activity and neurotoxicity screening, and potential compounds were screened out for further determination of ED50, TD50 and in vitro binding experiments. Finally, compound 5,7-Bis(pentyloxy)-[1,2,4]triazolo[1,5-a]pyrimidine (6b) with best activity and lowest toxicity was obtained. The pharmacological results showed that the ED50 of compound 6b was MES = 11.3 mg/kg, PTZ = 9.5 mg/kg, which was superior to that of the carbamazepine (MES = 6.3 mg/kg) and ethosuximide (PTZ = 3.6 mg/kg). The IC50 of compound 6b binding affinity toward the GABAA receptor was 0.15 mu M, and the GABA content experiments showed that compound 6b significantly increased the GABA content in the rat brain. In elevated plus maze (EPM) assay, compound 6b possessed anxiolytic effects. In silico studies, most of the target compounds have suitable physicochemical and pharmacokinetic data with the possibility of drug-forming properties, molecular docking results showed that compound 6b could generate more interactions with the amino acid residues of diazepam active site of GABAA receptor.