A COMPARISON OF RO-16-6028 WITH BENZODIAZEPINE RECEPTOR FULL AGONISTSON GABA(A) RECEPTOR FUNCTION

Ro 16-6028 (bretazenil) has a pharmacological profile characteristic o f a partial agonist at the gamma-aminobutyric acid, (GABA(A)) receptor -linked benzodiazepine site. The present study utilized modulation of [S-35]t-butylbicyclophosphorothionate ([S-35]TBPS) binding and enhance ment of GABA-stimulated Cl-36- uptake to further assess Ro 16-6028's p artial agonist profile in vitro. Ro 16-6028 was the most potent benzod iazepine examined, exhibiting an IC50 (concentration at which half-max imal inhibition of specific [S-35]TBPS binding occurs) of 6.1 nM, comp ared to clonazepam (7.9 nM), flunitrazepam (13.6 nM) and diazepam (91. 1 nM). The rank order of potency for inhibition of [S-35]TBPS binding was identical to that for inhibition of [H-3]flunitrazepam binding. Ho wever, Ro 16-6028 was less efficacious in that it produced 27% inhibit ion of specific [S-35]TBPS binding, compared to clonazepam (34%), flun itrazepam (41%) or diazepam (49%). Ro 16-6028 antagonized the inhibiti on of [S-35]TBPS binding produced by 10 muM diazepam. Ro 16-6028 was a lso more potent and less efficacious than diazepam in potentiating GAB A-stimulated Cl-36- uptake. These results provide further evidence tha t Ro 16-6028 is acting as a partial agonist at the benzodiazepine rece ptor in modulating function of the GABA(A) receptor complex.