title: Imidazenil, a new partial agonist of benzodiazepine receptors, reverses the inhibitory action of isoniazid and stress on gamma-aminobutyric acidA receptor function.
abstract: The imidazobenzodiazepine 6-(2-bromophenyl)-8-fluoro-4H-imidazo-[1,5-a] [1,4]benzodiazepine-3-carboxamide (imidazenil) is a new anxiolytic and anticonvulsant ligand of the benzodiazepine recognition site that possesses the characteristics of a partial allosteric modulator of the gamma-aminobutyric acid (GABA) type A receptor. The effects of imidazenil on GABAA receptor function were examined both in vitro and in vivo. Imidazenil inhibited [3H] flumazenil binding to mouse cerebral cortical membranes in vitro with an IC50 of 0.9 nM, showing that this compound binds with high affinity to benzodiazepine receptors. However, imidazenil failed to modify t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to washed or unwashed mouse cortical membrane preparations. Furthermore, imidazenil injected i.p. into mice failed to affect [35S]TBPS binding subsequently measured in unwashed cortical membranes. In contrast, imidazenil reduced in a dose-dependent manner the increase in [35S]TBPS binding elicited by isoniazid (200 mg/kg s.c.), an effect mimicked by lorazepam and abecarnil++ but not by bretazenil. As expected, i.p. administration of lorazepam or abecarnil induced within 30 min a marked reduction in [35S]TBPS binding subsequently measured in unwashed cortical membranes of control mice. Moreover, imidazenil at a dose as low as 0.05 mg/kg (i.p.) delayed the onset of convulsions and death elicited by isoniazid and reduced significantly the number of mice exhibiting seizures. Accordingly, imidazenil also showed great potency in antagonizing the convulsions induced by pentylenetetrazole in rats. Imidazenil also completely abolished the increase in [35S]TBPS binding induced by foot-shock or exposure to carbon dioxide. Finally, imidazenil antagonized both in vitro and in vivo the effects of bretazenil or lorazepam on GABAA receptor function.
authors.affiliation: Department of Experimental Biology, University of Cagliari, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Serra
authors.forename: C A
authors.initials: CA
authors.lastname: Ghiani
authors.forename: C
authors.initials: C
authors.lastname: Motzo
authors.forename: T
authors.initials: T
authors.lastname: Cuccheddu
authors.forename: S
authors.initials: S
authors.lastname: Floris
authors.forename: P
authors.initials: P
authors.lastname: Giusti
authors.forename: G
authors.initials: G
authors.lastname: Biggio
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000037:antagonists & inhibitors / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants / Q000037:antagonists & inhibitors / Q000378:metabolism; D005442:Flumazenil / Q000378:metabolism; D058787:GABA-A Receptor Antagonists; D007093:Imidazoles / Q000494:pharmacology*; D007538:Isoniazid / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced; D013312:Stress, Physiological / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D013462:Sulfur Radioisotopes; D014316:Tritium
chemical_list: D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D058787:GABA-A Receptor Antagonists; D007093:Imidazoles; D011963:Receptors, GABA-A; D013462:Sulfur Radioisotopes; D014316:Tritium; D001569:Benzodiazepines; D005442:Flumazenil; C037476:tert-butylbicyclophosphorothionate; C082661:imidazenil; D007538:Isoniazid; D010433:Pentylenetetrazole