N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists: X-ray Crystallography, Structure-Affinity Relationships and in vitro Pharmacology

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Among the ionotropic glutamatereceptors, the physiological role of kainate receptors is less well understood. Althoughligands with selectivity towards the kainate receptor subtype GluK1 are available,tool compounds with selectivity at the remaining kainate receptor subtypes are sparse.Here, we have synthesized a series of quinoxaline-2,3-diones with substitutions in theN1-, 6- and 7-position to investigate the structure-activity relationship (SAR) at GluK1-3and GluK5. Pharmacological characterization at native and recombinant kainate and AMPAreceptors revealed that compound 37 had a GluK3-binding affinity (Ki) of 0.142 μMand 8-fold preference for GluK3 over GluK1. Despite lower binding affinity of 22 atGluK3 (Ki = 2.91 μM) its preference for GluK3 over GluK1and GluK2 was >30-fold.Compound 37 was crystallized with the GluK1 ligand-binding domain to understand the SAR.The X-ray structure showed that 37 stabilized the protein inan open conformation, consistent with an antagonist binding mode.

Original languageEnglish
JournalA C S Chemical Neuroscience
Pages (from-to)1841-1853
Number of pages13
Publication statusPublished - 20 Mar 2019

ID: 194250477