title: Relationship between benzodiazepine receptor occupancy and potentiation of gamma-aminobutyric acid-stimulated chloride flux in vitro of four ligands of differing intrinsic efficacies.
abstract: Intrinsic efficacy is the inherent ability of a ligand to induce the conformational change of its receptor that is required to transduce the event of signal recognition into a physiologically relevant response. Relating fractional receptor occupancy to fractional effect is an indirect but reliable way to assess relative intrinsic efficacy. The receptor studied was the benzodiazepine receptor (BZR), a modulatory site on the gamma-aminobutyric acidA (GABAA) receptor-chloride channel. The relationship between fractional BZR occupancy, as assessed by inhibition of [3H]flumazenil binding, and potentiation of GABA-stimulated 36Cl- influx into membrane vesicles of rat cerebral cortex was evaluated for four ligands under identical experimental conditions. Triazolam and the quinolizinone Ro 19-8022 potentiated the effect of GABA maximally by nearly 50%, diazepam by about 40% and bretazenil by approximately 20%. Potentiation of GABA-stimulated 36Cl- flux by 25% was observed at about 35% BZR occupancy for diazepam, about 45% for triazolam and about 95% for Ro 19-8022. Bretazenil did not produce 25% potentiation even at receptor saturation. Although the curves relating fractional BZR occupancy to GABA potentiation were hyperbolic and nearly superimposable for triazolam and diazepam, those for Ro 19-8022 and bretazenil displayed parabolic characteristics by inducing an effect only at very high BZR occupancy, reflecting the partial agonistic profile of the latter two compounds. The rank order of relative intrinsic efficacy determined in this study was: triazolam congruent to diazepam much greater than Ro 19-8022 greater than bretazenil.
authors.affiliation: Pharma Division-Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Facklam
authors.forename: P
authors.initials: P
authors.lastname: Schoch
authors.forename: W E
authors.initials: WE
authors.lastname: Haefely
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology*; D004357:Drug Synergism; D005442:Flumazenil / Q000378:metabolism; D008024:Ligands; D008297:Male; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D014229:Triazolam / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D001570:Benzodiazepinones; D002712:Chlorides; D008024:Ligands; D011963:Receptors, GABA-A; D014229:Triazolam; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; C054626:bretazenil; D003975:Diazepam