Pharmacological characterization of the novel anxiolytic beta-carboline abecarnil in rodents and primates.
beta-Carboline abecarnil was behaviorally and biochemically characterized as a new anxiolytic agent in rodents and primates in comparison with the benzodiazepine (BZ) anxiolytics. Oral treatment with abecarnil (0.5-10 mg/kg) showed a potent anticonflict activity in the water-lick test in rats. The minimal effective dose was lower than those of BZ anxiolytics, such as etizolam, diazepam, clotiazepam and tofisopam. Abecarnil also showed taming effects to suppress fighting and aggressive behaviors in mice and monkeys with little sedative and ataxic effects, in contrast to the BZ anxiolytics producing marked sedative and ataxic effects. Furthermore, abecarnil suppressed both the sedative and ataxic effects induced by diazepam. Abecarnil bound to rat cerebellar BZ1 receptors (Ki = 0.24 nM) with higher affinity than to rat spinal cord BZ2 receptors (Ki = 1.3 nM), whereas BZ derivatives bound to both the receptors with a low and equal affinity. GABA-ratios of abecarnil were 1.9 for the BZ1 receptors and 2.8 for the BZ2 receptors, and they were smaller than those of diazepam and flunitrazepam. Thus, in contrast to the BZ derivatives, abecarnil may act as a selective partial agonist at central BZ1 receptors, resulting in its potent anticonflict and taming effects with little sedative and ataxic effects.
Ozawa
M
M
Research Department, Nihon Schering K.K. Osaka, Japan.
Nakada
Y
Y
Sugimachi
K
K
Yabuuchi
F
F
Akai
T
T
Mizuta
E
E
Kuno
S
S
Yamaguchi
M
M
D000374:Aggression / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D001667:Binding, Competitive; D002243:Carbolines / Q000378:metabolism / Q000494:pharmacology*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005442:Flumazenil / Q000378:metabolism; D006591:Hexobarbital / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000145:classification / Q000187:drug effects / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014316:Tritium
D014151:Anti-Anxiety Agents; D002243:Carbolines; D011963:Receptors, GABA-A; D014316:Tritium; D001569:Benzodiazepines; D005442:Flumazenil; D006591:Hexobarbital; C062769:abecarnil