6fz4
From Proteopedia
Structure of GluK1 ligand-binding domain in complex with N-(7-fluoro-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)-2-hydroxybenzamide at 1.85 A resolution
Structural highlights
Function[GRIK1_RAT] Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus.[1] Publication Abstract from PubMedAmong 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 muM and 8-fold preference for GluK3 over GluK1. Despite lower binding affinity of 22 at GluK3 ( Ki = 2.91 muM), 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. N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists: X-ray Crystallography, Structure-Affinity Relationships, and in Vitro Pharmacology.,Pallesen J, Mollerud S, Frydenvang K, Pickering DS, Bornholdt J, Nielsen B, Pasini D, Han L, Marconi L, Kastrup JS, Johansen TN ACS Chem Neurosci. 2019 Mar 20;10(3):1841-1853. doi:, 10.1021/acschemneuro.8b00726. Epub 2019 Jan 23. PMID:30620174[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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