3,5-DIHYDRO-4H-2,3-BENZODIAZEPINE-4-THIONES - A NEW CLASS OF AMPA RECEPTOR ANTAGONISTS

Synthesis and evaluation of anticonvulsant activity of a series of 2,3 -benzodiazepin-4-ones (2) chemically related to -methyl-7,8-(methylene dioxy)-5H-2,3-benzodiazepine (1, GYKI 52466) have been reported in our recent publications. Compounds 2 manifested marked anticonvulsant pro perties acting as mino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic a cid (AMPA) receptor antagonists. In an attempt to better define the st ructure-activity relationships (SAR) and to obtain more potent and sel ective anticonvulsant agents, 1-aryl-3,5-dihydro-4H-2,3-benzodiazepine -4-thiones 3 were synthesized from the corresponding isosteres 2. The evaluation is reported of their anticonvulsant effects, both in the au diogenic seizures test with DBA/2 mice and against the maximal electro shock- and pentylenetetrazole-induced seizures in Swiss mice. New deri vatives 3 showed higher potency, less toxicity and longer-lasting anti convulsant action than those of the parent compounds 2 in all tests em ployed. Analogous to derivatives 2, new compounds 3 do not affect the benzodiazepine receptor (BZR) while they do antagonize AMPA-induced se izures; their anticonvulsant activity is reversed by pretreatment with aniracetam but not with flumazenil, thus suggesting a clear involveme nt of AMPA receptors. Electrophysiological data indicate a noncompetit ive blocking mechanism at the AMPA receptor sites for 3i, the most act ive of the series and over 5-fold more potent than 1.