Binding Mode of an 伪-Amino Acid-Linked Quinoxaline-2,3-dione Analogue at Glutamate Receptor Subtype GluK1

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• 作者：Charles S. Demmer ; Charlotte M酶ller ; Patricia M. G. E. Brown ; Liwei Han ; Darryl S. Pickering ; Birgitte Nielsen ; Derek Bowie ; Karla Frydenvang ; Jette S. Kastrup ; Lennart Bunch
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：June 17, 2015
• 年：2015
• 卷：6
• 期：6
• 页码：845-854
• 全文大小：471K
• ISSN：1948-7193

文摘

Two 伪-amino acid-functionalized quinoxalines, 1a (CNG-10301) and 1b (CNG-10300), of a quinoxaline moiety coupled to an amino acid moiety were designed, synthesized, and characterized pharmacologically. While 1a displayed low affinity at native AMPA, KA, and NMDA receptors, and at homomeric GluK1,3 receptors, the affinity for GluK2 was in the midmicromolar range (K_i = 136 渭M), 1b displayed low to midmicromolar range binding affinity at all the iGluRs (K_i = 9鈥?26 渭M). In functional experiments (outside-out patches excised from transfected HEK293T cells), 100 渭M 1a partially blocked GluK1 (33% peak response), while GluK2 was unaffected (96% peak response). Furthermore, 1a was shown not to be an agonist at GluK1 and GluK2 at 100 渭M. On the other hand, 100 渭M 1b fully antagonized GluK1 (8% peak response) but only partially blocked GluK2 (33% peak response). An X-ray structure at 2.3 脜 resolution of 1b in the GluK1-LBD (ligand-binding domain) disclosed an unexpected binding mode compared to the predictions made during the design phase; the quinoxaline moiety remains to act as an amino acid bioisostere, but the amino acid moiety is oriented into a new area within the GluK1 receptor. The structure of the GluK1-LBD with 1b showed a large variation in domain openings of the three molecules from 25掳 to 49掳, demonstrating that the GluK1-LBD is capable of undergoing major domain movements.