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), pyrazoloquinol ones (CGS), 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones (PIs) 1, an d abecarnil were studied after intraperitoneal (IP) administration in mice. The anticonvulsant effects were evaluated on seizures evoked by means of a uditory 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 > q uazepam > prazepam > halazepam > If > le > Ib > CGS 9896 > Ic > Ih, and la, the latter being inactive against audiogenic seizures. Some PIs 1 and abec arnil showed anticonvulsant properties against seizures induced by PTZ with a potency lower than that observed in audiogenic seizures. The pharmacolog ical actions of Id, If, and ii were significantly reduced by a treatment wi th flumazenil (8.24 mu mol/kg IF), suggesting a clear involvement of benzod iazepine mechanisms in the anticonvulsant activity of these compounds or th eir metabolites. The anticonvulsant activity of Id, If, and ii was also eva luated against seizures induced by two beta-carbolines namely methyl-beta-c arboline-3-carboxylate (beta-CCM) and methyl-6,7-dimethoxy-4-ethyl-beta-car boline-3-carboxyl (DMCM), in DBA/2 mice: they gave better protection agains t seizures induced by beta-CCM than the ones by DMCM. The potency of variou s BDZs and PIs as inhibitors of specific [H-3]flumazenil binding to neurona l membranes, was also evaluated. The radioligand binding study, carried out on stable cell lines expressing definite combinations of benzodiazepine re ceptor subunits, demonstrated that Ib, le, Id, and Ih have preferential int eraction with alpha(1), beta(3), gamma(2), receptor subtypes. (C) 2000 Else vier Science.