期刊
ACS CHEMICAL NEUROSCIENCE
卷 6, 期 6, 页码 845-854出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.5b00038
关键词
Design; synthesis; radioligand binding X-ray crystallography; domain opening
资金
- Lundbeck Foundation
- Carlsberg Foundation
- University of Copenhagen Programme of Excellence (GluTarget)
- Horsley Foundation
- Danscatt
Two alpha-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 (Ki = 136 mu M), 1b displayed low to midmicromolar range binding affinity at all the iGluRs (K-i = 9-126 mu M). In functional experiments (outside-out patches excised from transfected HEK293T cells), 100 mu 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 mu M. On the other hand, 100 mu M 1b fully antagonized GluK1 (8% peak response) but only partially blocked GluK2 (33% peak response). An X-ray structure at 2.3 angstrom 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 degrees G; to 49 degrees, demonstrating that the GluK1-LBD is capable of undergoing major domain movements.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据