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.
Guan
Li-Ping
LP
School of Food, Drug & Medicine Zhejiang Ocean University, Zhoushan, Zhejiang Province 316004, PR China. glp730@yahoo.com.cn
Sui
Xin
X
Deng
Xian-Qing
XQ
Quan
Ying-Chun
YC
Quan
Zhe-Shan
ZS
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045442:Rotarod Performance Test; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000927:Anticonvulsants; D011724:Pyridazines; D014230:Triazoles