Synthesis and anticonvulsant activity of a new 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine

A series of 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine derivatives were synthesized. In initial screening and quantitative evaluation, compound 2r was among the most active agents, exhibiting in the same time the lowest toxicity. In the anti-maximal electroshock test, it showed median effective dose (ED50) of 17.3 mg/kg and median toxicity dose (TD50) of 380.3 mg/kg, and the protective index (PI) of 22.0, which is much better than PI of the reference drugs. In a subsequent test, compound 2r had median hypnotic dose (HD50) of 746.6 mg/kg, thus demonstrating much better margin of safety compared to reference drugs. Compound 2r also showed oral activity against MES-induced seizures and lower oral neurotoxicity. For explanation of the putative mechanism of action, compound 2r was tested in chemical induced models.

Graphical abstract6-Alkoxy-[1,2,4]triazolo[4,3-b]pyridazine derivatives were designed and synthesized. Their anticonvulsant activities were investigated by the maximal electroshock test and their neurotoxicity was evaluated by the rotarod neurotoxicity test. Figure optionsDownload full-size imageDownload as PowerPoint slide