Szymańska Ewa, Chałupnik Paulina, Johansen Tommy N, Nielsen Birgitte, Cuñado Moral Ana Maria, Pickering Darryl S, Więckowska Anna, Kieć-Kononowicz Katarzyna
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Kraków, Poland.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Chem Biol Drug Des. 2017 Dec;90(6):1271-1281. doi: 10.1111/cbdd.13048. Epub 2017 Jul 18.
A series of racemic unnatural amino acids was rationally designed on the basis of recently published X-ray structures of the GluA2 LBD with bound phenylalanine-based antagonists. Twelve new diaryl- or aryl/heteroaryl-substituted phenylalanine derivatives were synthesized and evaluated in vitro in radioligand binding assays at native rat ionotropic glutamate receptors. The most interesting compound in this series, (RS)-2-amino-3-(3'-hydroxy-5-(1H-pyrazol-4-yl)-[1,1'-biphenyl]-3-yl)propanoic acid 7e, showed the binding affinity of 4.6 μm for native AMPA receptors and over fourfold lower affinity for kainic acid receptors. Furthermore, 7e was evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. Recently reported X-ray structures 5CBR and 5CBS, representing two distinct antagonist binding modes, were used as templates for molecular docking of the synthesized series. Binding data supported with molecular modeling confirmed that aryl/heteroaryl-substituted phenylalanine analogues effectively bind to AMPA receptors with low micromolar affinity and high selectivity over native NMDA and kainate receptors. These properties make 7e a promising lead for the further development of new AMPA receptor ligands.
基于最近发表的与结合苯丙氨酸类拮抗剂的 GluA2 配体结合域（LBD）的 X 射线结构，合理设计了一系列外消旋非天然氨基酸。合成了 12 种新的二芳基或芳基/杂芳基取代的苯丙氨酸衍生物，并在天然大鼠离子型谷氨酸受体的放射性配体结合试验中进行了体外评估。该系列中最有趣的化合物，（RS）-2-氨基-3-（3'-羟基-5-（1H-吡唑-4-基）-[1,1'-联苯]-3-基）丙酸 7e，对天然 AMPA 受体的结合亲和力为 4.6 μM，对 kainic 酸受体的亲和力低四倍以上。此外，还在重组同源大鼠 GluA2 和 GluA3 受体上对 7e 进行了评估。最近报道的代表两种不同拮抗剂结合模式的 X 射线结构 5CBR 和 5CBS 被用作合成系列分子对接的模板。分子建模支持的结合数据证实，芳基/杂芳基取代的苯丙氨酸类似物能以低微摩尔亲和力和对天然 NMDA 和 kainate 受体的高选择性有效地结合到 AMPA 受体上。这些特性使 7e 成为进一步开发新型 AMPA 受体配体的有前途的先导化合物。
