title: 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K) and related compounds: structure-activity relationships for the AMPA-type non-NMDA receptor.
abstract: A novel series of quinoxalinediones possessing imidazolyl and related heteroaromatic substituents was synthesized and evaluated for their activity to inhibit [3H]AMPA binding from rat whole brain. From the structure-activity relationships, it was found that the 1H-imidazol-1-yl moiety could function as a bioisostere for the cyano and nitro groups, and that 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (11) showed the most potent activity for the AMPA receptor. Compound 11 was evaluated for selectivity versus other excitatory amino acid receptors, and its action against AMPA at its receptor in the rat striatum was characterized. These data showed that compound 11 was a selective antagonist for the AMPA receptor with a Ki value of 0.084 microM, being approximately equipotent with 2,3-dihydro-6-nitro-7-sulfamoylbenzo(f)quinoxaline (3) (NBQX; Ki = 0.060 microM). Compound 11 was also found to give protection against sound-induced seizure on DBA/2 mice at the minimum effective dose of 3 mg/kg ip (3; 10 mg/kg ip).
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Company Limited, Ibaraki, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Ohmori
authors.forename: S
authors.initials: S
authors.lastname: Sakamoto
authors.forename: H
authors.initials: H
authors.lastname: Kubota
authors.forename: M
authors.initials: M
authors.lastname: Shimizu-Sasamata
authors.forename: M
authors.initials: M
authors.lastname: Okada
authors.forename: S
authors.initials: S
authors.lastname: Kawasaki
authors.forename: K
authors.initials: K
authors.lastname: Hidaka
authors.forename: J
authors.initials: J
authors.lastname: Togami
authors.forename: T
authors.initials: T
authors.lastname: Furuya
authors.forename: K
authors.initials: K
authors.lastname: Murase
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000517:prevention & control; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D007093:Imidazoles; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C086162:6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione