A comparison of Ro 16-6028 with benzodiazepine receptor 'full agonists' on GABA_A receptor function

Ro 16-6028 (bretazenil) has a pharmacological profile characteristic of a partial agonist at the γ-aminobutyric acid_A (GABA_A) 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%antagonized the inhibition of [³⁵]TBPS binding produced by 10 μM, 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 GABA_A receptor complex.