title: YM90K: pharmacological characterization as a selective and potent alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor antagonist.
abstract: We investigated the pharmacological properties and neuroprotective actions of a novel alpha-amino-3-hydroxy-5-methylisoxazole-y-propionate (AMPA)/kainate receptor antagonist, [6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione hydrochloride (YM90K); formerly YM900], in comparison with those of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX). YM90K selectively displaced [3H]-AMPA binding (Ki = 0.084 microM) and was less potent in inhibiting [3H]-kainate (Ki = 2.2 microM), [3H]-L-glutamate (N-methyl-D-aspartate-sensitive site; Ki > 100 microM) and [3H]-glycine (strychnine-insensitive site; Ki = 37 microM) binding to rat brain membranes. YM90K co-injected with AMPA or kainate into the rat striatum protected cholinergic neurons against AMPA- or kainate-induced neurotoxicity. YM90K showed potent suppressive activity against audiogenic seizure in DBA/2 mice; ED50 values of YM90K and NBQX against tonic seizure were 2.54 and 7.17 mg/kg (i.p.), respectively. The duration of the anticonvulsant effects of YM90K and NBQX was 30 min, indicating that both compounds possess short action. In a global ischemia model, YM90K (15 mg/kg i.p. x 3), NBQX (30 mg/kg i.p. x 3) and CNQX (60 mg/kg i.p. x 3) significantly prevented the delayed neuronal death in the hippocampal CA1 region in Mongolian gerbils when administered 1 h after 5-min ischemia. In addition, the therapeutic time window for the neuroprotective effect of YM90K (30 mg/kg i.p. x 3) was 6 h. In a focal ischemia model, YM90K (30 mg/kg i.v. bolus+10 mg/kg/h for 4 h) reduced the volume of ischemic damage in the cerebral cortex in F344 rats. Thus, YM90K was shown to be a potent and selective antagonist for AMPA/kainate receptors in vitro and in vivo. This compound may provide a therapeutic effect in various neurodegenerative disorders such as ischemic stroke in which glutamate neurotoxicity is thought to play a critical role in neuronal damage.
authors.affiliation: Neuroscience Laboratory, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Shimizu-Sasamata
authors.forename: S
authors.initials: S
authors.lastname: Kawasaki-Yatsugi
authors.forename: M
authors.initials: M
authors.lastname: Okada
authors.forename: S
authors.initials: S
authors.lastname: Sakamoto
authors.forename: S
authors.initials: S
authors.lastname: Yatsugi
authors.forename: J
authors.initials: J
authors.lastname: Togami
authors.forename: K
authors.initials: K
authors.lastname: Hatanaka
authors.forename: J
authors.initials: J
authors.lastname: Ohmori
authors.forename: K
authors.initials: K
authors.lastname: Koshiya
authors.forename: S
authors.initials: S
authors.lastname: Usuda
authors.forename: K
authors.initials: K
authors.lastname: Murase
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy; D002544:Cerebral Infarction / Q000188:drug therapy; D003342:Corpus Striatum / Q000098:blood supply / Q000187:drug effects; D005849:Gerbillinae; D007511:Ischemia / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011810:Quinoxalines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000188:drug therapy
chemical_list: D000927:Anticonvulsants; D011810:Quinoxalines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C086162:6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione