(S)-2-氨基-3-(5-甲基-3-羟基异恶唑-4-基)丙酸 (AMPA) 和 kainate 受体配体：生物等排体替换的进一步探索以及结构和生物学研究。
( S)-2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic Acid (AMPA) and Kainate Receptor Ligands: Further Exploration of Bioisosteric Replacements and Structural and Biological Investigation.
机构信息
Department of Biotechnology, Chemistry and Pharmacy, (DoE 2018-2022) NatSynDrugs , University of Siena , Via A. Moro 2 , 53100 Siena , Italy.
Department of Pharmacy , University of Napoli Federico II , Via D. Montesano 49 , 80131 Napoli , Italy.
出版信息
J Med Chem. 2018 Mar 8;61(5):2124-2130. doi: 10.1021/acs.jmedchem.8b00099. Epub 2018 Feb 26.
Starting from 1-4 and 7 structural templates, analogues based on bioisosteric replacements (5a-c vs 1, 2 and 6 vs 7) were synthesized for completing the SAR analysis. Interesting binding properties at GluA2, GluK1, and GluK3 receptors were discovered. The requirements for GluK3 interaction were elucidated by determining the X-ray structures of the GluK3-LBD with 2 and 5c and by computational studies. Antinociceptive potential was demonstrated for GluK1 partial agonist 3 and antagonist 7 (2 mg/kg ip).
从 1-4 和 7 个结构模板开始，基于生物等排替换（5a-c 与 1，2 和 6 与 7）合成类似物以完成 SAR 分析。在 GluA2、GluK1 和 GluK3 受体上发现了有趣的结合特性。通过确定 GluK3-LBD 与 2 和 5c 的 X 射线结构以及计算研究，阐明了与 GluK3 相互作用的要求。GluK1 部分激动剂 3 和拮抗剂 7（2mg/kg ip）表现出抗伤害感受潜能。
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