New non competitive AMPA antagonists

New halogen atom substituted 2,3-benzodiazepine derivatives condensed with an azole ring on the seven membered part of the ring system of type 3 and 4 as well as 5 and 6 were synthesized. It was found that chloro-, dichloro- and bromo-substitutions in the benzene ring and additionally imidazole ring condensation on the diazepine ring can successfully substitute the methyle ne-dioxy group in the well known molecules GYKI 52456 (1) and GYKI 53773 (2 ) and the 3-acetyl-4-methyl structural feature in 2, respectively, preservi ng the highly active AMPA antagonist characteristic of the original molecul es. From the most active compounds (3b,i) 3b (GYKI 47261) was chosen for de railed investigations. 3b revealed an excellent, broad spectrum anticonvuls ant activity against seizures evoked by electroshock and different chemocon vulsive agents indicating a possible antiepileptic efficacy. 3b was found t o be highly active in a transient model of focal ischemia predictive of a t herapeutic value in human stroke. 3b also reversed the dopamine depleting e ffect of MPTP and antagonized the oxotremorine induced tremor in mice indic ating a potential antiparkinson activity. (C) 2000 Elsevier Science Ltd. Al l rights reserved.