Ohno Kazushige, Tsutsumi Rie, Matsumoto Naoyuki, Yamashita Hiroshi, Amada Yoko, Shishikura Jun-ichi, Yatsugi Hiroshi Inami Shin-Ichi, Okada Masamichi, Sakamoto Shuichi, Yamaguchi Tokio
Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba 305-8585, Japan.
J Pharmacol Exp Ther. 2003 Jul;306(1):66-72. doi: 10.1124/jpet.103.049973. Epub 2003 Mar 26.
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.
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体被认为在多种神经疾病的发病机制以及正常脑功能中发挥重要作用。寻找作为潜在治疗药物的AMPA受体拮抗剂的工作正在进行中。在此，我们描述了一种新型非竞争性AMPA受体拮抗剂2-[N-(4-氯苯基)-N-甲基氨基]-4H-吡啶并[3,2-e]-1,3-噻嗪-4-酮（YM928）的功能特性。该化合物在原代大鼠海马培养物中抑制AMPA受体介导的毒性，IC50为2微摩尔/升。随着激动剂浓度增加，其抑制方式为非竞争性。YM928在培养细胞中阻断AMPA诱导的细胞内钙内流，IC50为3微摩尔/升，并拮抗AMPA诱导的内向电流，IC50为1微摩尔/升。YM928在大鼠脑膜中既不取代[3H]AMPA结合，也不取代其他现有的谷氨酸受体相关配体结合。就体内活性而言，YM928在以3毫克/千克口服给药45分钟后，对DBA/2小鼠的声音诱发惊厥具有抗惊厥作用。因此，YM928有潜力作为治疗各种类型神经疾病的口服治疗药物。
