Evaluation of two anticonvulsant amino-pyridazine derivatives in the conflict test in rats

A Perio, JP Chambon, R Calassi, M Heaulme and K Biziere

Two amino-phenyl-pyridazine derivatives, SR 41378 and CM 40907, have been reported to antagonize seizures in mice, rats and Papio papio baboons with comparable potencies. Structurally, SR 41378 differs from CM 40907 by an additional chlorine in position 6 of the phenyl ring. In the present study the activity of these two compounds in the operant approach-avoidance conflict test in rats was examined and compared with that of diazepam, pentobarbital, meprobamate and valproate. SR 41378 increased punished responding, a measure of anticonflict activity (ED50 = 5.2 mg/kg), and decreased nonpunished responding, a measure of sedative activity, with a threshold active dose of 20 mg/kg i.p. The overall potency of SR 41378 was comparable to that of pentobarbital. CM 40907 (10-40 mg/kg i.p.) did not affect punished responding and decreased nonpunished responding at the dose of 40 mg/kg i.p. The duration of the anticonflict activity of SR 41378 increased with the dose and lasted over 4 h at the 20-mg/kg i.p. dose. At this dose, sedation lasted 1 h. An increase in anticonflict potency and tolerance to sedation were observed after a 5-day treatment with SR 41378 (20 mg/kg i.p.). The anticonflict and sedative activities of SR 41378 were not antagonized by Ro 15-1788 or CGS 8216. In vitro SR 41378 did not interact with benzodiazepine receptor sites. In conclusion, although CM 40907 and SR 41378 exhibit similar anticonvulsant activities, the present study reveals a major pharmacological difference between the two compounds because SR 41378 also possesses anticonflict properties.

Volume 239, Issue 2, pp. 542-547, 11/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics