Anxiolytic-like effects of PNU-101017, a partial agonist at the benzodiazepine receptor.
PNU-101017 is a chemically novel ligand at the benzodiazepine recognition site of cloned GABAA receptors. It was reported to potentiate GABA-mediated chloride current in cultured cells with a moderate intrinsic activity and a biphasic dose-response relationship. In this study, we confirmed that PNU-101017 has a partial agonist-like effect in the antagonism of metrazole-induced seizures in mice. It produced no sedation or ataxia, but did antagonize diazepam-induced motor deficit of mice in the rotarod test. PNU-101017 was weakly active in anti-conflict anxiolytic tests, but attenuated the plasma corticosteroid response to mild stress in rats. It also antagonized stress-induced elevation of cerebellar cGMP levels in mice. Like chlordiazepoxide, it increased drinking of saline solution in thirsty rats. PNU-101017 did not potentiate the CNS-depressant effects of ethanol, and produced no evidence of physical dependence when administered repeatedly. Agonists with low intrinsic activity at the benzodiazepine receptor, such as PNU-101017, should be further explored for therapeutic uses.
Tang
A H
AH
Pharmacia & Upjohn Inc., Kalamazoo, MI 49001, USA.
Franklin
S R
SR
Carter
D B
DB
Sethy
V H
VH
Needham
L M
LM
Jacobsen
E J
EJ
Von Voigtlander
P F
PF
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D003220:Conflict, Psychological; D003345:Corticosterone / Q000097:blood; D006152:Cyclic GMP / Q000378:metabolism; D003975:Diazepam / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004327:Drinking Behavior / Q000187:drug effects; D004597:Electroshock; D000431:Ethanol / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D010433:Pentylenetetrazole / Q000009:adverse effects / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology*; D011863:Radioimmunoassay; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D013312:Stress, Physiological / Q000503:physiopathology
C104547:7-chloro-5((cis-3,5-dimethylpiperazine)carbonyl)imidazo(1,5a)quinoline-3-carboxylate; D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D011804:Quinolines; D011963:Receptors, GABA-A; D000431:Ethanol; D006152:Cyclic GMP; D003975:Diazepam; D003345:Corticosterone; D010433:Pentylenetetrazole