title: Synthesis of anticonvulsive AMPA antagonists: 4-oxo-10-substituted-imidaz.
abstract: The overstimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been implicated in the physiopathogenesis of epilepsy as well as in acute and chronic neurodegenerative disorders. An original series of readily water soluble 4-oxo-10-substituted-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives was synthesized. The most potent derivative 6a exhibited nanomolar binding affinity (IC50 = 35nM) and antagonist activity (IC50 = 6nM) at ionotropic AMPA receptor. This compound also demonstrated potent anticonvulsant properties in MES in mice and rats with long durations of action with ED50 values in the 1-3 mg/kg dose range following ip and iv administration.
authors.affiliation: Aventis Pharma S.A., Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Stutzmann
authors.forename: G A
authors.initials: GA
authors.lastname: Bohme
authors.forename: A
authors.initials: A
authors.lastname: Boireau
authors.forename: D
authors.initials: D
authors.lastname: Damour
authors.forename: M W
authors.initials: MW
authors.lastname: Debono
authors.forename: A
authors.initials: A
authors.lastname: Genevois-Borella
authors.forename: P
authors.initials: P
authors.lastname: Jimonet
authors.forename: J
authors.initials: J
authors.lastname: Pratt
authors.forename: J C
authors.initials: JC
authors.lastname: Randle
authors.forename: Y
authors.initials: Y
authors.lastname: Ribeill
authors.forename: M
authors.initials: M
authors.lastname: Vuilhorgne
authors.forename: S
authors.initials: S
authors.lastname: Mignani
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000494:pharmacology; D014981:Xenopus
chemical_list: D000927:Anticonvulsants; D002264:Carboxylic Acids; D007546:Isoquinolines; D011719:Pyrazines; D011810:Quinoxalines; D018091:Receptors, AMPA; D013777:Tetrazoles; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C086162:6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione; C082309:tezampanel