title: New non competitive AMPA antagonists.
abstract: 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 methylenedioxy group in the well known molecules GYKI 52466 (1) and GYKI 53773 (2) and the 3-acetyl-4-methyl structural feature in 2, respectively, preserving the highly active AMPA antagonist characteristic of the original molecules. From the most active compounds (3b,i) 3b (GYKI 47261) was chosen for detailed investigations. 3b revealed an excellent, broad spectrum anticonvulsant activity against seizures evoked by electroshock and different chemoconvulsive agents indicating a possible antiepileptic efficacy. 3b was found to be highly active in a transient model of focal ischemia predictive of a therapeutic value in human stroke. 3b also reversed the dopamine depleting effect of MPTP and antagonized the oxotremorine induced tremor in mice indicating a potential antiparkinson activity.
authors.affiliation: Institute for Drug Research, Ltd, Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Abrahám
authors.forename: S
authors.initials: S
authors.lastname: Sólyom
authors.forename: E
authors.initials: E
authors.lastname: Csuzdi
authors.forename: P
authors.initials: P
authors.lastname: Berzsenyi
authors.forename: I
authors.initials: I
authors.lastname: Ling
authors.forename: I
authors.initials: I
authors.lastname: Tarnawa
authors.forename: T
authors.initials: T
authors.lastname: Hámori
authors.forename: I
authors.initials: I
authors.lastname: Pallagi
authors.forename: K
authors.initials: K
authors.lastname: Horváth
authors.forename: F
authors.initials: F
authors.lastname: Andrási
authors.forename: G
authors.initials: G
authors.lastname: Kapus
authors.forename: L G
authors.initials: LG
authors.lastname: Hársing
authors.forename: I
authors.initials: I
authors.lastname: Király
authors.forename: M
authors.initials: M
authors.lastname: Patthy
authors.forename: G
authors.initials: G
authors.lastname: Horváth
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D007608:Kainic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018721:Muscarinic Agonists / Q000494:pharmacology; D010095:Oxotremorine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012160:Retina / Q000187:drug effects / Q000502:physiology; D012640:Seizures / Q000139:chemically induced; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D018721:Muscarinic Agonists; D018091:Receptors, AMPA; C418824:GYKI 47261; C061950:GYKI 52466; D001569:Benzodiazepines; D010095:Oxotremorine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid