IMIDAZENIL, A NEW PARTIAL AGONIST OF BENZODIAZEPINE RECEPTORS, REVERSES THE INHIBITORY-ACTION OF ISONIAZID AND STRESS ON GAMMA-AMINOBUTYRICACID(A) RECEPTOR FUNCTION

The imidazobenzodiazepine 6-(2-bromophenyl)-8-fluoro-4H-imidazo-[1,5-a ] [1,4]benzodiazepine-3-carboxamide (imidazenil) is a new anxiolytic a nd anticonvulsant ligand of the benzodiazepine recognition site that p ossesses the characteristics of a partial allosteric modulator of the gamma-aminobutyric acid (GABA) type A receptor. The effects of imidaze nil on GABA(A) receptor function were examined both in vitro and in vi vo. Imidazenil inhibited [H-3] flumazenil binding to mouse cerebral co rtical membranes in vitro with an IC50 of 0.9 nM, showing that this co mpound binds with high affinity to benzodiazepine receptors. However, imidazenil failed to modify t-[S-35]butylbicyclophosphorothionate ([S- 35]TBPS) binding to washed or unwashed mouse cortical membrane prepara tions. Furthermore, imidazenil injected i.p. into mice failed to affec t [S-35]TBPS binding subsequently measured in unwashed cortical membra nes. In contrast, imidazenil reduced in a dose dependent manner the in crease in [S-35]TBPS binding elicited by isoniazid (200 mg/kg s.c.), a n effect mimicked by lorazepam and abecarnil but not by bretazenil. As expected, i.p. administration of lorazepam or abecarnil induced withi n 30 min a marked reduction in [S-35]TBPS binding subsequently measure d 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 convulsion s and death elicited by isoniazid and reduced significantly the number of mice exhibiting seizures. Accordingly, imidazenil also showed grea t potency in antagonizing the convulsions induced by pentylenetetrazol e in rats. Imidazenil also completely abolished the increase in [S-35] TBPS binding induced by foot-shock or exposure to carbon dioxide. Fina lly, imidazenil antagonized both in vitro and in vivo the effects of b retazenil or lorazepam on GABAA receptor function.