Partial and full agonists/inverse agonists affect [ 35S]TBPS binding at different occupancies of central benzodiazepine receptors

Abstract

Concentration-dependent effects of benzodiazepine receptor ligands were examined on nonequilibrium binding of t-butylbicyclophosphoro[ 35S]thionate (TBPS, 20 min of incubation at 25°C) to synaptosomal membranes of rat cerebral cortex. Benzodiazepine receptor occupancies were calculated from the displacing potencies of the ligands determined for [ 3H]flumazenil binding under identical conditions. Greater maximal enhancing (i.e. accelerating) effects of the full agonists diazepam and flunitrazepam on [ 35S]TBPS binding were reached at lower occupancies of benzodiazepine receptors than the smaller enhancing effects of the partial agonists bretazenil and the β-carboline ZK 91296. Similarly, the maximal decreasing effect of the full inverse agonist methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) on TBPS binding was reached at lower occupancy than that of the partial inverse agonist FG 7142. Half-maximal effects on TBPS binding corresponded to about 20–30% occupancies for the full agonists and DMCM, while for partial agonists and FG 7142 they exceeded 60–80% occupancies. Different (concave versus convex) shapes of the occupancy-effect curves can also differentiate partial from full agonists and inverse agonists. The results suggest that different pharamcological efficacies of benzodiazepine receptor ligands are associated with differences in coupling between benzodazepine and convulsant binding sites to modulate the chloride ionophores.