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.