Full and partial agonism displayed by benzodiazepine receptor ligands at recombinant gamma-aminobutyric acidA receptor subtypes.
The differences in intrinsic activity and receptor subtype specificity of the newly developed benzodiazepine receptor ligands bretazenil, divaplon and abecarnil were assessed in recombinant gamma-aminobutyric acidA (GABAA) receptors expressed in mammalian cells from the subunit-cDNA combinations alpha 3 beta 2 gamma 2 and alpha 5 beta 2 gamma 2. Chloride currents induced by rapid application of GABA in the presence or absence of drugs were measured using the whole-cell configuration of the patch-clamp technique. Bretazenil displayed an intrinsic activity which amounted only to 58 +/- 7% and 35 +/- 11% of that of flunitrazepam at the alpha 3 beta 2 gamma 2 and alpha 5 beta 2 gamma 2 combination, respectively. The maximum potentiation by divaplon was only 28 +/- 5% and 21 +/- 9% of that of flunitrazepam at the respective subunit combinations. Thus, the partial agonism postulated for bretazenil and divaplon on pharmacological grounds is shown to be operative on the level of single GABAA receptors. Most strikingly, abecarnil potentiated the GABA response to the same degree as flunitrazepam at the alpha 3 beta 2 gamma 2 combination but to only 52 +/- 14% compared to flunitrazepam at the alpha 5 beta 2 gamma 2 combination. This finding demonstrates that the intrinsic activity of benzodiazepine receptor ligands can vary among the receptor subtypes with the degree of receptor modulation being influenced by the type of alpha subunit.
University of Zurich, Institute of Pharmacology, Switzerland.
F
F
Knoflach
U
U
Drescher
L
L
Scheurer
P
P
Malherbe
H
H
Mohler
D001570:Benzodiazepinones / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D004357:Drug Synergism; D005445:Flunitrazepam / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D046911:Macromolecular Substances; D011743:Pyrimidines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics; D012680:Sensitivity and Specificity; D013379:Substrate Specificity; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D001570:Benzodiazepinones; D002243:Carbolines; D007093:Imidazoles; D008024:Ligands; D046911:Macromolecular Substances; D011743:Pyrimidines; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; C060714:divaplon; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; D004247:DNA; C062769:abecarnil; C054626:bretazenil