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

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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.

Original languageEnglish
Pages (from-to)255-260
Number of pages6
JournalEuropean Journal of Pharmacology: Molecular Pharmacology
Volume246
Issue number3
DOIs
Publication statusPublished - Aug 15 1993

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GABA-A Receptors
Carbolines
ZK 91296
Ligands
Flunitrazepam
Convulsants
Flumazenil
Ionophores
Diazepam
Cerebral Cortex
Chlorides
Binding Sites
Membranes
tert-butylbicyclophosphorothionate
methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate
FG 7142

Keywords

  • Agonists/inverse agonists (Partial and full)
  • Allosteric regulation of efficacy
  • Benzodiazepine receptors
  • GABA receptor-ionophore complex
  • [S]TBPS binding (t-butylbicyclophosphoro[S]thionate)

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "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.",
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AU - Maksay, G.

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N2 - 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.

AB - 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.

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