2 research outputs found
N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists: X-ray Crystallography, Structure-Affinity Relationships and in vitro Pharmacology
Among the ionotropic
glutamate receptors, the physiological role of kainate receptors is
less well understood. Although ligands with selectivity toward 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 the N1-, 6-, and 7-position to investigate
the structure–activity relationship (SAR) at GluK1–3
and GluK5. Pharmacological characterization at native and recombinant
kainate and AMPA receptors revealed that compound 37 had
a GluK3-binding affinity (Ki) of 0.142
μM and 8-fold preference for GluK3 over GluK1. Despite lower
binding affinity of 22 at GluK3 (Ki = 2.91 μM), its preference for GluK3 over GluK1 and
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 in an open conformation,
consistent with an antagonist binding mode