1-ARYL-3,5-DIHYDRO-4H-2,3-BENZODIAZEPIN-4-ONES - NOVEL AMPA RECEPTOR ANTAGONISTS

Our previous publication (Eur. J. Pharmacol. 1995, 294, 411-422) repor ted preliminary chemical and biological studies of some 2,3-benzodiaze pines, analogues of -aminophenyl)4-methyl-7,8-(methylenedioxy)-5H-2,3- benzodiazepines (1, GYKI 52466), which have been shown to possess sig nificant anticonvulsant activity. This paper describes the synthesis o f new 1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones and the evaluatio n of their anticonvulsant effects. The observed findings extend the st ructure-activity relationships previously suggested for this class of anticonvulsants. The seizures were evoked both by means of auditory st imulation in DBA/2 mice and by pentylenetetrazole or maximal electrosh ock in Swiss mice. Aminophenyl)- (38) and (3'-aminophenyl)-3,5-dihydro -7,8-dimethoxy-4H-2,3- benzodiazepin-4-one (39), the most active compo unds of the series, proved to be more potent than 1 in all tests emplo yed. In particular, the ED(50) values against tonus evoked by auditory stimulation were 12.6 mu mol/kg for derivative 38, 18.3 mu mol/kg for 39, and 25.3 mu mol/kg for 1. Higher doses were necessary to block to nic extension induced both by maximal electroshock and by pentylenetet razole. In addition these compounds exhibited anticonvulsant propertie s that were longer lasting than those of compound 1 and were less toxi c. The novel 2,3-benzodiazepines were also investigated for a possible correlation between their anticonvulsant activities against convulsio ns induced by amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and their affinities for benzodiazepine receptors (BZR). The 2, 3-benzodiazepines did not affect the binding of [H-3]flumazenil to BZR , and conversely, their anticonvulsant effects were not reversed by fl umazenil. On the other hand the 2,3-benzodiazepines antagonized seizur es induced by AMPA and aniracetam in agreement with an involvement of the AMPA receptor. In addition, both the derivative 38 and the compoun d 1 markedly reduced the AMPA receptor-mediated membrane currents in g uinea-pig olfactory cortical neurons in vitro in a noncompetitive mann er. The derivatives 25 and 38-40 failed to displace specific ligands f rom N-methyl-D-aspartate (NMDA), AMPA/kainate, or metabotropic glutama te receptors.