Functional Characterization of YM928, a Novel Noncompetitive α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist
| Autor: | Kazushige Ohno, Yoko Amada, Tokio Yamaguchi, Rie Tsutsumi, Shuichi Sakamoto, Naoyuki Matsumoto, Masamichi Okada, Hiroshi Yamashita, Hiroshi Inami Shin-Ichi Yatsugi, Jun-Ichi Shishikura |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
Agonist Pyridines medicine.drug_class Thiazines AMPA receptor Pharmacology Binding Competitive Calcium in biology Mice Radioligand Assay In vivo medicine Animals Receptors AMPA Rats Wistar Receptor alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid IC50 Cells Cultured Kainic Acid Chemistry Glutamate receptor Antagonist Rats Mice Inbred DBA Molecular Medicine Calcium Excitatory Amino Acid Antagonists |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 306:66-72 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|