Role of cGMP in the mechanism of anxiolytic activity of U-78875.
The inhibition constant (Ki) of U-78875 was investigated without and with muscimol in the incubation medium using in vitro (3H)-flunitrazepam [(3H)-FNZ] binding to cortical membrane preparation. Also, the effect of U-78875 on cerebellar cyclic 3',5'-guanosine monophosphate (cGMP) was studied in control and stressed (electric footshock) mice. The Ki of U-78875 was 1.56 nM for inhibition of (3H)-FNZ binding. The presence of muscimol (10(-5) M) had no significant effect on the Ki of U-78875. U-78875 and diazepam significantly decreased cerebellar cGMP, and this effect was antagonized by flumazenil. Both U-78875 and diazepam dose-dependently antagonized electric footshock-induced increases in cGMP, and U-78875 was two orders of magnitude more potent in stressed animals as compared to control animals. These biochemical investigations indicate that U-78875 is an agonist of benzodiazepine receptors, and cGMP may mediate its anxiolytic activity.
CNS Research, Upjohn Company, Kalamazoo, MI 49001.
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D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D005445:Flunitrazepam / Q000378:metabolism; D008297:Male; D051379:Mice; D009118:Muscimol / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013315:Stress, Psychological / Q000378:metabolism
D014151:Anti-Anxiety Agents; D002243:Carbolines; D003292:Convulsants; D010069:Oxadiazoles; D011810:Quinoxalines; D009118:Muscimol; D005445:Flunitrazepam; D006152:Cyclic GMP; C036150:beta-carboline-3-carboxylic acid methyl ester; D003975:Diazepam; C069443:panadiplon