TY - JOUR T1 - Functional Characterization of YM928, a Novel Noncompetitive α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 66 LP - 72 DO - 10.1124/jpet.103.049973 VL - 306 IS - 1 AU - Kazushige Ohno AU - Rie Tsutsumi AU - Naoyuki Matsumoto AU - Hiroshi Yamashita AU - Yoko Amada AU - Jun-Ichi Shishikura AU - Hiroshi Inami Shin-Ichi Yatsugi AU - Masamichi Okada AU - Shuichi Sakamoto AU - Tokio Yamaguchi Y1 - 2003/07/01 UR - http://jpet.aspetjournals.org/content/306/1/66.abstract N2 - The α-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 μM. Its manner of inhibition was noncompetitive as the agonist concentration was increased. YM928 blocked AMPA-induced intracellular calcium influx with an IC50 of 3 μM and antagonized AMPA-induced inward currents with an IC50 of 1 μM 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. The American Society for Pharmacology and Experimental Therapeutics ER -