F 2692: flumazenil-reversible anxiolytic effects but inactive on [3H]-Ro 15-4513 binding

F 2692, a pyridazine derivative, has little affinity for benzodiazepine receptors, yet in two animal tests its anxiolytic effects have been reported to be reversed by benzodiazepine antagonists. In the rat social interaction test, after 5 days of IP treatment, F 2692 (3, 10, or 30 mg/kg) produced greater increases in social interaction than diazepam (0.3, 1, or 3 mg/kg). A comparison of acute and 5 day administration of F 2692 showed rapidly developing tolerance at all doses. The acute anxiolytic effects of F 2692 (1 mg/kg) were reversed by the benzodiazepine antagonists flumazenil (4 mg/kg) and ZK 93426 (4 mg/kg). We, therefore, examined whether F 2692 was active at a benzodiazepine binding site (the diazepam-insensitive portion of [3H]-Ro 15-4513) to which flumazenil but not flunitrazepam binds. However, F 2692 (10(-9) to 10(-4) M) was without effect on this binding. Thus, F 2692 has anxiolytic actions in the social interaction test, that are greater than those of diazepam, and which can be reversed by benzodiazepine antagonists. However, the site of action of the compound remains unknown.