A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15-1788, benzodiazepine tranquilizers, ?-carbolines, and phenobarbitone

Abstract

The potent benzodiazepine receptor ligands beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) and the corresponding methylester (beta-CCM) administered i.v. depressed segmental dorsal root potentials in spinal cats, reversed the prolongation of dorsal root potentials by phenobarbitone, and abolished the depression of a motor performance task induced by phenobarbitone in mice; beta-CCE enhanced the low-frequency facilitation of pyramidal population spikes in the hippocampus of anaesthetized rats. These effects of beta-carbolines reflect a depression of GABAergic synaptic transmission and, thus, are diametrically opposed to the enhancing action of benzodiazepine tranquilizers. The specific benzodiazepine antagonist, Ro 15-1788, while not affecting dorsal root potentials, hippocampal population spikes or phenobarbitone-induced motor performance depression, abolished the effects of beta-CCE on the three parameters and similar effects of beta-CCM on the spinal cord and motor performance. A three-state model of the benzodiazepine receptor is proposed in which benzodiazepine tranquilizers act as agonists enhancing the function of the benzodiazepine receptor as a coupling unit between GABA receptor and chloride channel, beta-carbolines act as "inverse agonists" reducing this coupling function, and Ro 15-1788 represents a competitive antagonist blocking both the enhancing effect of agonists and the depressant effect of "inverse agonists" on GABAergic synaptic transmission.

Acute and chronic effects of the benzodiazepine receptor ligand FG 7142: proconvulsant properties and kindling

“…the 1-carbolines (Nutt et al, 1982a). In order to distinguish these two types the first group have come to be known as 'inverse agonists' (Polc et al, 1982) or 'contragonists' (Nutt, 1983) and the second group as conventional or 'neutral' antagonists. One of the contragonists, FG 7142, which is proconvulsant (Petersen et al, 1983) and anxiogenic in animals File & Pellow, 1984) has been shown in man to produce severe anxiety and panic (Dorow et al, 1983).…”

Modulation of 5‐hydroxytryptamine‐induced head‐twitch response by drugs acting at GABA and related receptors

“…Benzodiazepine receptor ligands showed the expected profile. Diazepam potentiated head-twitching (as reported by Nakamura & Fukushima, 1977) and the 'inverse agonist' PCCE (Polc et al, 1982) inhibited it. Rol 5-1788 is a benzodiazepine with antagonistic effects against both classic benzodiazepines and 'inverse agonists' (Hunkeler et al, 1981).…”

β-Carbolines Selectively Antagonize the Cholecystokinin Action in Isolated Guinea-Pig Gallbladder Muscle

“…8-Carbolines have been purported to act as inverse agonists with regard to BZP receptors (12) since it has been evidenced to bind to these receptors (9,11), to reverse BZP action (9-11, 16, 17) and to be antagonized by a BZP antagonist, Ro 15 1788 (18,19). Therefore, l3-carbolines and BZP are expected to have a certain common feature from the structural point of view on the binding to the BZP receptor.…”