In rodents, the effect of the beta-carboline derivative isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate (abecarnil), a new ligand for benzodiazepine receptors possessing anxiolytic and anticonvulsant properties, was evaluated on the function of central gamma-aminobutyric acid (GABA)A receptor complex, both in vitro and in vivo. Added in vitro to rat cortical membrane preparation, abecarnil increased [H-3]GABA binding, enhanced muscimol-stimulated Cl-36- uptake and reduced the binding of t-[S-35]butylbicyclophosphorothionate ([S-35]TBPS). These effects were similar to those induced by diazepam, whereas the partial agonist Ro 16-6028 {tert-butyl-(S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]-pyrrolo-[2,1-c][1,4]benzodiazepine-1-carboxylate} showed very weak efficacy in these biochemical tests. After i.p. injection to rats, abecarnil and diazepam decreased in a time-dependent and dose-related (0.25-20 mg/kg i.p.) manner [S-35]TBPS binding measured ex vivo in the cerebral cortex. Moreover, both drugs at the dose of 0.5 mg/kg antagonized completely the convulsant activity and the increase of [S-35]TBPS binding induced by isoniazid (350 mg/kg s.c.) as well as the increase of [S-35]TBPS binding induced by foot-shock stress. To better correlate the biochemical and the pharmacological effects, we studied the action of abecarnil on [S-35]TBPS binding, exploratory motility and on isoniazid-induced biochemical and pharmacological effects in mice. In these animals, abecarnil produced a paralleled dose-dependent (0.05-1 mg/kg i.p.) reduction of both motor behavior and cortical [S-35]TBPS binding. Moreover, 0.05 mg/kg of this beta-carboline reduced markedly the increase of [S-35]TBPS binding and the convulsions induced by isoniazid (200 mg/kg s.c.). These results demonstrate that abecarnil enhances GABAergic transmission with an efficacy similar to or even greater than diazepam, a full agonist of the benzodiazepine receptor. In contrast, the partial agonist Ro 16-6028 has much lower efficacy both in vivo and in vitro experiments.
Pharmacology of gamma-aminobutyric acid(A) receptor complex after the in vivo administration of the anxioselective and anticonvulsant beta-carboline derivative abecarnil
SERRA, MARIANGELA;Foddi M. C;CONCAS, ALESSANDRA;
1992-01-01
Abstract
In rodents, the effect of the beta-carboline derivative isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate (abecarnil), a new ligand for benzodiazepine receptors possessing anxiolytic and anticonvulsant properties, was evaluated on the function of central gamma-aminobutyric acid (GABA)A receptor complex, both in vitro and in vivo. Added in vitro to rat cortical membrane preparation, abecarnil increased [H-3]GABA binding, enhanced muscimol-stimulated Cl-36- uptake and reduced the binding of t-[S-35]butylbicyclophosphorothionate ([S-35]TBPS). These effects were similar to those induced by diazepam, whereas the partial agonist Ro 16-6028 {tert-butyl-(S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]-pyrrolo-[2,1-c][1,4]benzodiazepine-1-carboxylate} showed very weak efficacy in these biochemical tests. After i.p. injection to rats, abecarnil and diazepam decreased in a time-dependent and dose-related (0.25-20 mg/kg i.p.) manner [S-35]TBPS binding measured ex vivo in the cerebral cortex. Moreover, both drugs at the dose of 0.5 mg/kg antagonized completely the convulsant activity and the increase of [S-35]TBPS binding induced by isoniazid (350 mg/kg s.c.) as well as the increase of [S-35]TBPS binding induced by foot-shock stress. To better correlate the biochemical and the pharmacological effects, we studied the action of abecarnil on [S-35]TBPS binding, exploratory motility and on isoniazid-induced biochemical and pharmacological effects in mice. In these animals, abecarnil produced a paralleled dose-dependent (0.05-1 mg/kg i.p.) reduction of both motor behavior and cortical [S-35]TBPS binding. Moreover, 0.05 mg/kg of this beta-carboline reduced markedly the increase of [S-35]TBPS binding and the convulsions induced by isoniazid (200 mg/kg s.c.). These results demonstrate that abecarnil enhances GABAergic transmission with an efficacy similar to or even greater than diazepam, a full agonist of the benzodiazepine receptor. In contrast, the partial agonist Ro 16-6028 has much lower efficacy both in vivo and in vitro experiments.
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