title: Benzodiazepine antagonist Ro 15-1788: binding characteristics and interaction with drug-induced changes in dopamine turnover and cerebellar cGMP levels.
abstract: The recently discovered benzodiazepine antagonist Ro 15-1788 was characterized in binding studies, and its potency and selectivity were determined in vivo by interaction with drug-induced changes in dopamine turnover and cerebellar cGMP level. Ro 15-1788 reduced [3H]flunitrazepam binding in the brain in vivo with a potency similar to that of diazepam and effectively inhibited [3H]diazepam binding in vitro (IC50 = 2.3 +/- 0.6 nmol/liter). [3H]Ro 15-1788 bound to tissue fractions of rat cerebral cortex with an apparent dissociation (KD) of 1.0 +/- 0.1 nmol/liter. The in vitro potency of various benzodiazepines in displacing [3H]Ro 15-1788 from its binding site was of the same rank order as found previously in [3H]diazepam binding. Autoradiograms of [3H]Ro 15-1788 binding in sections of rat cerebellum showed the same distribution of radioactivity as with [3H]flunitrazepam. The attenuating effect of diazepam on the chlorpromazine- or stress-induced elevation of homovanillic acid in rat brain was antagonized by Ro 15-1788. Among a series of compounds which either decreased or increased the rat cerebellar cGMP level, only the effect of benzodiazepine receptor ligands (diazepam, zopiclone, CL 218 872) was antagonized by Ro 15-1788. Thus, Ro 15-1788 is a selective benzodiazepine antagonist acting at the level of the benzodiazepine receptor in the central nervous system. Peripheral benzodiazepine binding sites in kidney and schistosomes were not affected by Ro 15-1788.
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism*; D001570:Benzodiazepinones / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D003975:Diazepam / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005442:Flumazenil; D005445:Flunitrazepam / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D011955:Receptors, Drug / Q000378:metabolism*; D011963:Receptors, GABA-A
chemical_list: D001570:Benzodiazepinones; D011955:Receptors, Drug; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D005445:Flunitrazepam; D006152:Cyclic GMP; D003975:Diazepam; D004298:Dopamine