title: A comparison of Ro 16-6028 with benzodiazepine receptor 'full agonists' on GABAA receptor function.
abstract: Ro 16-6028 (bretazenil) has a pharmacological profile characteristic of a partial agonist at the gamma-aminobutyric acidA (GABAA) receptor-linked benzodiazepine site. The present study utilized modulation of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding and enhancement of GABA-stimulated 36Cl- uptake to further assess Ro 16-6028's partial agonist profile in vitro. Ro 16-6028 was the most potent benzodiazepine examined, exhibiting an IC50 (concentration at which half-maximal inhibition of specific [35S]TBPS binding occurs) of 6.1 nM, compared to clonazepam (7.9 nM), flunitrazepam (13.6 nM) and diazepam (91.1 nM). The rank order of potency for inhibition of [35S]TBPS binding was identical to that for inhibition of [3H]flunitrazepam binding. However, Ro 16-6028 was less efficacious in that it produced 27% inhibition of specific [35S]TBPS binding, compared to clonazepam (34%), flunitrazepam (41%) or diazepam (49%). Ro 16-6028 antagonized the inhibition of [35S]TBPS binding produced by 10 microM diazepam. Ro 16-6028 was also more potent and less efficacious than diazepam in potentiating GABA-stimulated 36Cl- uptake. These results provide further evidence that Ro 16-6028 is acting as a partial agonist at the benzodiazepine receptor in modulating function of the GABAA receptor complex.
authors.affiliation: Department of Pharmacology, College of Medicine, University of California, Irvine 92717.
authors.forename: D A
authors.initials: DA
authors.lastname: Finn
authors.forename: K W
authors.initials: KW
authors.lastname: Gee
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D013462:Sulfur Radioisotopes
chemical_list: D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D011963:Receptors, GABA-A; D013462:Sulfur Radioisotopes; C037476:tert-butylbicyclophosphorothionate; C054626:bretazenil