SYNTHESIS AND ANTICONVULSANT PROPERTIES OF NEW BENZYLPYRIDAZINE DERIVATIVES

Several 3-substituted pyridazines and a series of imidazo- and triazol opyridazines were synthesized and tested for anticonvulsant activity a gainst maximal electroshock-induced seizures in mice. The most active derivatives, 3-ureidopyridazine 7 and triazolopyridazines 16, 18, 21, and 25 with oral ED(50)'s that ranged from 6.2 to 22.0 mg/kg, were mor e extensively investigated by evaluating their ability to prevent chem ically induced seizures and were compared with phenytoin, phenobarbita l, sodium valproate, carbamazepine, and diazepam. dichlorobenzyl)-6-me thyltriazolo-[4,3-b]pyridazine (25) was also protective in the pentyle netetrazole-induced seizures test (ED(50) 76 mg/kg per os) and blocked strychnine-induced tonic extensor seizures (ED(50) = 34.5 mg/kg per o s). Furthermore, derivative 25 showed anticonvulsant effects on bicucu lline- and yohimbine-induced seizures tests in mice. All these results suggest that the pharmacological activity of 25 is partly due to modi fications of glycinergic and GABAergic transmission. Moreover, molecul ar modeling studies based on the antiepileptic drug lamotrigine and th e most stable conformer of 25 show structural similarities between the se two molecules. This conformer also agrees with the electronic toler ances and volume of benzodiazepine pharmacophore models.