title: Stereospecific transduction of behavioral effects via diazepam-insensitive GABAA receptors.
abstract: Previous studies reported a positive correlation between ligand affinities at diazepam-insensitive GABAA receptors and substitution for the discriminative stimulus effects of the benzodiazepine receptor antagonist, flumazenil, in pigeons. In the present experiments, bretazenil and Ro 14-5974 (ethyl-(S)-11,12,13,13 a-tetrahydro-9-oxo-9H-imidazo[1,5-a]-pyrrolo-[2,1-c] [1,4]benzodiazepine-1-carboxylate) partially substituted for, and blocked the discriminative stimulus effects of midazolam, congruent with their actions at diazepam-sensitive GABAA receptors in vitro. In addition, bretazenil and Ro 14-5974, but not their R-enantiomers, had high affinity for diazepam-insensitive receptors and fully substituted for the discriminative stimulus effects of flumazenil. The R-enantiomers of these compounds had low affinity (Ki > 1 microM) for diazepam-sensitive and diazepam-insensitive receptors, and did not share discriminative stimulus effects with flumazenil or midazolam. Ro 19-0528 (7-chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-met hyl-6H- imidazo[1,5-a][1,4]benzodiazepin-6-one), a structurally related compound with full agonist actions at diazepam-sensitive GABAA receptors, had high diazepam-insensitive receptor affinity (Ki = 96 nM) and partially substituted for the discriminative stimulus effects of flumazenil. These results are consistent with stereospecific mediation of the discriminative stimulus effects of flumazenil through high affinity binding to diazepam-insensitive receptors in pigeons.
authors.affiliation: Psychobiology Section, National Institute on Drug Abuse, Addiction Research Center, Baltimore, MD 21224, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Acri
authors.forename: G
authors.initials: G
authors.lastname: Wong
authors.forename: J M
authors.initials: JM
authors.lastname: Witkin
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D010856:Columbidae; D003975:Diazepam / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D005442:Flumazenil / Q000378:metabolism / Q000494:pharmacology; D018757:GABA Modulators / Q000378:metabolism / Q000494:pharmacology; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000378:metabolism / Q000494:pharmacology; D010069:Oxadiazoles / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012680:Sensitivity and Specificity; D013237:Stereoisomerism
chemical_list: D001570:Benzodiazepinones; D018757:GABA Modulators; D007093:Imidazoles; D010069:Oxadiazoles; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C096581:Ro 19-0528; D005442:Flumazenil; C096580:Ro 14-5974; C054626:bretazenil; D003975:Diazepam; D008874:Midazolam