1-methyl-beta-carboline-3-carboxylic-acid and propyl-beta-carboline-3-carboxylate

t-Butylbicyclophosphorothionate (TBPS) produces dose-dependent enhancement of [3H]propyl beta-carboline-3-carboxylate ([3H]PCC, 40 pM) binding to the benzodiazepine1 (BZ1) receptor subtype in hippocampus. Furthermore, TBPS enhancement of [3H]PCC binding was antagonized by micromolar concentrations of gamma-aminobutyric acid (GABA) in a way reversible by bicuculline. BZ receptor ligands that are "GABA positive" (i.e., enhance GABA neurotransmission) allosterically inhibited [35S]TBPS binding, whereas "GABA-negative" ligands (i.e., inhibit GABA neurotransmission) produced the opposite effect. The efficacy of the ligands as modulators of [35S]TBPS binding was consistent with their reported in vivo pharmacology. The effects of positive and negative ligands on [35S]TBPS binding were modulated by micromolar concentrations of GABA. Examination of the kinetics of [35S]TBPS binding suggested the presence of slowly and rapidly dissociating components. The GABA-positive clonazepam stabilized the rapidly dissociating component of [35S]TBPS binding, whereas methyl beta-carboline-3-carboxylate had a similar effect on the slowly dissociating component. It is speculated that the slowly dissociating component of [35S]TBPS binding is associated with a closed chloride channel, whereas the opposite is proposed for the rapidly dissociating component. The differential effects of GABA-positive versus GABA-negative ligands on [35S]TBPS binding and the modulatory effect of GABA provide further evidence to suggest that [35S]TBPS labels a site near the chloride ionophore linked to the GABA-BZ receptor complex.

Topics: Animals; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Bridged-Ring Compounds; Carbolines; Cerebral Cortex; Chlorides; Clonazepam; gamma-Aminobutyric Acid; In Vitro Techniques; Ionophores; Kinetics; Ligands; Male; Rats; Rats, Inbred Strains; Receptors, GABA-A; Sulfur Radioisotopes; Tritium

Injected i.v. into baboons, Ro 15-1788 (a benzodiazepine antagonist) and propyl-beta-carboline-3-carboxylate did not modify either the behavior or the electroencephalogram at doses up to 2 mg/kg. Methyl-beta-carboline-3-carboxylate is a potent convulsant at doses of 20 micrograms/kg in photosensitive baboons and 100 micrograms/kg in non-photosensitive baboons. These convulsive doses of methyl-beta-carboline-3-carboxylate are effectively antagonized by 0.5 mg/kg of Ro 15-1788 and also by 2 mg/kg of propyl-beta-carboline-3-carboxylate.

Topics: Animals; Benzodiazepinones; Carbolines; Diazepam; Flumazenil; Indoles; Papio; Photosensitivity Disorders; Seizures; Time Factors

The effects of the methyl, ethyl and propyl esters of beta-carboline-3-carboxylic acid have been studied in vitro and in vivo. All three esters were found to be potent inhibitors of 3H-flunitrazepam binding in the rat cerebellum and cerebral cortex in vitro. In vivo, the methyl and ethyl esters were potent proconvulsant agents, whereas the propyl ester was not. Furthermore, the methyl ester produced convulsions which were blocked by the ethyl and propyl esters as well as by diazepam. These in vivo differences may be due to the beta-carboline esters having different proportions of agonistic and antagonistic actions at their recognition sites.

Topics: Animals; Carbolines; Cerebellum; Cerebral Cortex; Electroshock; Indoles; Male; Muridae; Seizures

The effects of the methyl, ethyl and propyl esters of beta-carboline-3-carboxylic acid were assessed on low affinity binding of GABA to rat brain membranes, and the enhancement of such binding by diazepam. The propyl ester acted as a benzodiazepine agonist in enhancing low affinity GABA binding, while the methyl and ethyl esters acted as benzodiazepine antagonists in reversing the stimulation of GABA binding by diazepam. These effects on low affinity GABA binding in vitro are consistent with pharmacological and behavioural actions of these esters in vivo and support the hypothesis that such actions are mediated via a GABA-benzodiazepine receptor complex.

Topics: Animals; Brain; Carbolines; Diazepam; gamma-Aminobutyric Acid; In Vitro Techniques; Indoles; Membranes; Rats