title: Functional characterization of YM928, a novel moncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist.
abstract: The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is thought to play an important role in the pathogenesis of several neurological disorders as well as normal brain function. The search for AMPA receptor antagonists as potential therapeutics is ongoing. Here, we describe the functional characterization of a novel noncompetitive AMPA receptor antagonist, 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (YM928). This compound inhibited AMPA receptor-mediated toxicity in primary rat hippocampal cultures with an IC50 of 2 micro M. Its manner of inhibition was noncompetitive as the agonist concentration was increased. YM928 blocked AMPA-induced intracellular calcium influx with an IC50 of 3 micro M and antagonized AMPA-induced inward currents with an IC50 of 1 micro M in cultured cells. YM928 displaced neither [3H]AMPA binding nor other existing glutamate receptor-related ligand binding in rat brain membranes. In terms of in vivo activity, YM928 had an anticonvulsant effect in sound-induced seizures in DBA/2 mice 45 min after oral administration at 3 mg/kg. Thus, YM928 has potential as an oral therapeutic drug for various types of neurological disorders.
authors.affiliation: Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba 305-8585, Japan. ohno@yamanouchi.co.jp
authors.forename: Kazushige
authors.initials: K
authors.lastname: Ohno
authors.forename: Rie
authors.initials: R
authors.lastname: Tsutsumi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamashita
authors.forename: Yoko
authors.initials: Y
authors.lastname: Amada
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Shishikura
authors.forename: Hiroshi Inami Shin-Ichi
authors.initials: HI
authors.lastname: Yatsugi
authors.forename: Masamichi
authors.initials: M
authors.lastname: Okada
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Tokio
authors.initials: T
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011725:Pyridines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013843:Thiazines / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: C475769:2-(N-(4-chlorophenyl)-N-methylamino)-4H-pyrido(3,2-e)-1,3-thiazin-4-one; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D018091:Receptors, AMPA; D013843:Thiazines; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid; D002118:Calcium