title: Relative efficacies of 1,4-diazepines on GABA-stimulated chloride influx in rat brain vesicles.
abstract: The effects of 1,4-diazepines with two annelated heterocycles [brotizolam (WE 941), ciclotizolam (WE 973) and WE 1008] on gamma-aminobutyric acid (GABA)-stimulated chloride influx into rat brain membrane vesicles were examined. Brotizolam enhanced GABA (30 microM)-stimulated 36Cl- influx (146.1% of control), while ciclotizolam and WE 1008 showed only a small enhancement (119.3% and 119.1%, respectively) of GABA-stimulated 36Cl- uptake. Brotizolam resulted in a left shift of the GABA dose response curve at lower concentrations of GABA (10 microM), while at higher concentrations of GABA (1 mM), brotizolam caused a reduction of the maximal response. The enhancement of GABA-stimulated 36Cl- uptake by brotizolam (0.1 microM) was antagonized by Ro 15-1788. At higher concentration of GABA (300 microM), brotizolam inhibited GABA-stimulated 36Cl- uptake in a dose dependent manner and Ro15-1788 failed to antagonize this effect. These results suggest that 1) brotizolam produces an enhancement of GABA (30 microM)-stimulated chloride influx through the benzodiazepine receptor. 2) brotizolam inhibition of GABA (300 microM)-stimulated chloride influx involves an additional mechanism, and 3) the sedative-hypnotic action of brotizolam may be related to its high efficacy at the benzodiazepine/GABA-gated chloride channel.
authors.affiliation: Department of Pharmacology, University of Arizona Health Sciences Center, Tucson 85724.
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.forename: K H
authors.initials: KH
authors.lastname: Weber
authors.forename: W D
authors.initials: WD
authors.lastname: Bechtel
authors.forename: E
authors.initials: E
authors.lastname: Malatynska
authors.forename: H I
authors.initials: HI
authors.lastname: Yamamura
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D005442:Flumazenil / Q000494:pharmacology; D005445:Flunitrazepam / Q000494:pharmacology; D007700:Kinetics; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D014151:Anti-Anxiety Agents; D001381:Azepines; D002712:Chlorides; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; C020960:brotizolam; D005445:Flunitrazepam; C045448:We 1008; C045447:ciclotizolam