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 1i 1d 1f 1e 1b 1c 1h, and 1a, 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 1d, 1f, and 1i were significantly reduced by a treatment with flumazenil (8.24 micromol/kg IP), suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. The anticonvulsant activity of 1d, 1f, and 1i 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-carboxylate (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 [3H]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 1b, 1e, 1d, and 1h have preferential interaction with alpha(1), beta(3), gamma(2), receptor subtypes.
De Sarro
G
G
Chair of Pharmacology, Department of Experimental and Clinical Medicine, School of Medicine, University of Catanzaro, Catanzaro, Italy.
Carotti
A
A
Campagna
F
F
Mckernan
R
R
Rizzo
M
M
Falconi
U
U
Palluotto
F
F
Giusti
P
P
Rettore
C
C
De Sarro
A
A
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D005442:Flumazenil / Q000378:metabolism / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007659:Ketones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000517:prevention & control; D013574:Synaptosomes / Q000378:metabolism
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D006993:Hypnotics and Sedatives; D007211:Indoles; D007659:Ketones; D011720:Pyrazoles; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; C033830:2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one