Benzodiazepine receptor affinities, behavioral, and anticonvulsant activity of 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones in mice

The anticonvulsant properties of 1,4-benzodiazepines (BDZs), pyrazoloquinolones (CGS), 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones (PIs) 1, and abecarnil were studied after intraperitoneal (IP) administration in mice. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation in DBA/2 mice or on seizures induced by administration of pentylenetetrazole (PTZ) in Swiss mice. In DBA/2 mice abecarnil was the most potent compound studied. The rank order of potency for anticonvulsant activity was abecarnil > flunitrazepam > 1i > diazepam > pinazepam > Id > quazepam > prazepam > halazepam > If > le > Ib > CGS 9896 > Ic > Ih, and la, the latter being inactive against audiogenic seizures. Some PIs 1 and abecarnil showed anticonvulsant properties against seizures induced by PTZ with a potency lower than that observed in audiogenic seizures. The pharmacological actions of Id, If, and ii were significantly reduced by a treatment with flumazenil (8.24 mu mol/kg IF), suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. The anticonvulsant activity of Id, If, and ii was also evaluated against seizures induced by two beta-carbolines namely methyl-beta-carboline-3-carboxylate (beta-CCM) and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxyl (DMCM), in DBA/2 mice: they gave better protection against seizures induced by beta-CCM than the ones by DMCM. The potency of various BDZs and PIs as inhibitors of specific [H-3]flumazenil binding to neuronal membranes, was also evaluated. The radioligand binding study, carried out on stable cell lines expressing definite combinations of benzodiazepine receptor subunits, demonstrated that Ib, le, Id, and Ih have preferential interaction with alpha(1), beta(3), gamma(2), receptor subtypes. (C) 2000 Elsevier Science.