INVITRO CHARACTERIZATION OF BENZODIAZEPINE RECEPTOR AGONISTS, ANTAGONISTS, INVERSE AGONISTS AND AGONIST ANTAGONISTS

  • 1 January 1984
    • journal article
    • research article
    • Vol. 231  (3) , 572-576
Abstract
Using an extensively washed rat membrane preparation and standardized incubation conditions, the actions of benzodiazepine (BZ) receptor ligands were evaluated on [3H]flunitrazepam [+/-10 .mu.M .gamma. GABA], [3H]muscimol (+/-2.5 .mu.M etazolate) and [35S]butyl bicyclophosphorothionate (TBPS) binding. Classical BZ receptor agonists stimulated [35S]TBPS binding and [3H]muscimol binding in the presence of etazolate. These agents also possessed ratios for [3H]flunitrazepam binding in the absence and presence of GABA (GABA ratio) of 2-5. BZ antagonists and inverse agonists had GABA ratios less than 1 and did not alter, or reduced, both [35S]TBPS and [3H]muscimol (+etazolate) binding. The nonsedating BZ agonist/antagonist agents CGS 9896, CL 218872, PK 8165 and PK 9084 all possessed GABA ratios between 1.1 and 1.4 and only stimulated [35S]TBPS and [3H]muscimol (+etazolate) binding to approximately 50% of the level of classical BZ agonists. The BZ partial agonists CGS 9895 and RU 39419 both were unique in that they possessed GABA ratios of 1 or less, stimulated [35S]TBPS binding and had no effect on [3H]muscimol binding (+etazolate). By monitoring the major components of the BZ receptor complex (BZ receptor, GABA receptor and Cl channel), it was possible to distinguish between different BZ drugs and to support suggestions that these drugs act via unique BZ receptor populations which possess differential couplings to the GABA receptor and Cl channel.

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