PARTIAL AND FULL AGONISTS INVERSE AGONISTS AFFECT [S-35] TBPS BINDINGAT DIFFERENT OCCUPANCIES OF CENTRAL BENZODIAZEPINE RECEPTORS

Concentration-dependent effects of benzodiazepine receptor ligands wer e examined on nonequilibrium binding of t-butylbicyclophosphoro[S-35]t hionate (TBPS, 20 min of incubation at 25-degrees-C) to synaptosomal m embranes of rat cerebral cortex. Benzodiazepine receptor occupancies w ere calculated from the displacing potencies of the ligands determined for [H-3]flumazenil binding under identical conditions. Greater maxim al enhancing (i.e. accelerating) effects of the full agonists diazepam and flunitrazepam on [S-35]TBPS binding were reached at lower occupan cies of benzodiazepine receptors than the smaller enhancing effects of the partial agonists bretazenil and the beta-carboline ZK 91296. Simi larly, the maximal decreasing effect of the full inverse agonist methy l 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) on TBPS bi nding 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 par tial 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 re sults suggest that different pharmacological efficacies of benzodiazep ine receptor ligands are associated with differences in coupling betwe en benzodazepine and convulsant binding sites to modulate the chloride ionophores.