Functional characterization of YM928, a novel moncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist.
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.
Ohno
Kazushige
K
Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba 305-8585, Japan. ohno@yamanouchi.co.jp
Tsutsumi
Rie
R
Matsumoto
Naoyuki
N
Yamashita
Hiroshi
H
Amada
Yoko
Y
Shishikura
Jun-ichi
J
Yatsugi
Hiroshi Inami Shin-Ichi
HI
Okada
Masamichi
M
Sakamoto
Shuichi
S
Yamaguchi
Tokio
T
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
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