In rodents, the effect of the
beta-carboline derivative isopropyl-6- benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate (abecarrnil), 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 [3H]
GABA binding, enhanced
muscimol-stimulated 36Cl- uptake and reduced the binding of t-[35S]butylbicyclophosphorothionate ([35S]
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 [35S]
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 [35S]
TBPS binding induced by isoniazide (350 mg/kg s.c.) as well as the increase of [35S]
TBPS binding induced by foot-
shock stress. To better correlate the biochemical and the pharmacological effects, we studied the action of
abecarnil on [35S]
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 [35S]
TBPS binding. Moreover, 0.05 mg/kg of this
beta-carboline reduced markedly the increase of [35S]
TBPS binding and the convulsions induced by
isoniazid (200 mg/kg s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)