(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,Journal of Medicinal Chemistry

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(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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-16 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00099
Simone Brogi ₁ , Margherita Brindisi ₁ , Stefania Butini ₁ , Giridhar U Kshirsagar ₁ , Samuele Maramai ₁ , Giulia Chemi ₁ , Sandra Gemma ₁ , Giuseppe Campiani ₁ , Ettore Novellino ₂ , Paolo Fiorenzani ₃ , Jessica Pinassi ₃ , Anna Maria Aloisi ₃ , Mikko Gynther ₄ , Raminta Venskutonytė ₅ , Liwei Han ₅ , Karla Frydenvang ₅ , Jette Sandholm Kastrup ₅ , Darryl S Pickering ₅

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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).

中文翻译：

(S)-2-氨基-3-(5-甲基-3-羟基异恶唑-4-基)丙酸 (AMPA) 和红藻氨酸受体配体：生物等排替代的进一步探索以及结构和生物学研究

从1 – 4和7结构模板开始，合成基于生物等排替换的类似物（ 5a – c vs 1、2和6 vs 7 ）以完成 SAR 分析。发现了 GluA2、GluK1 和 GluK3 受体的有趣结合特性。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 GluK3 相互作用的要求。 GluK1 部分激动剂3和拮抗剂7 (2 mg/kg ip) 具有抗伤害潜力。

更新日期：2018-02-16

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