Behavioral effects of U-78875, a quinoxalinone anxiolytic with potent benzodiazepine antagonist activity.
U-78875 (3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl) imidazo[1,5-a]-quinoxalin-4(5H)-one) is a chemically novel compound with a high affinity for the benzodiazepine receptors. It has anticonflict effects in both the Vogel and Cook-Davidson models of anxiety, with a potency similar to that of diazepam (1-3 mg/kg, i.p.). In unanesthetized rats implanted with cortical electrodes for EEG recording, i.p. injections of U-78875 (3-10 mg/kg) increased the EEG power density in frequencies above 12 Hz, and decreased EEG power at lower frequencies. This EEG effect is similar to that of diazepam, and was completely antagonized by pretreatment with flumazenil. In animal models measuring central nervous system depression, U-78875 is much weaker than diazepam. It produced minimal impairment of rotarod performance in rats at doses up to 30 mg/kg, but at lower doses completely reversed the impairment from 10 mg/kg of diazepam. In rats trained to avoid shocks in a shuttle box, U-78875 (3-10 mg/kg) increased avoidance responses and antagonized the suppression of avoidance from diazepam (10 mg/kg). In the mouse one-trial passive avoidance task, pretreatment with U-78875 (1-10 mg/kg) before training produced no anterograde amnesia, but completely blocked the amnesic effect from diazepam (10 mg/kg). The diazepam antagonist potency for U-78875 is 10 to 100 times that of flumazenil. This unusual profile of mixed agonist/antagonist activities suggests U-78875 to be a unique anxiolytic agent with a minimum of central nervous system depression.
CNS Research, Upjohn Company, Kalamazoo, Michigan.
A H
AH
Tang
S R
SR
Franklin
C S
CS
Himes
P M
PM
Ho
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D003975:Diazepam / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004569:Electroencephalography; D005442:Flumazenil / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010069:Oxadiazoles / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
D014151:Anti-Anxiety Agents; D010069:Oxadiazoles; D011810:Quinoxalines; D005442:Flumazenil; D003975:Diazepam; C069443:panadiplon