6SBT

Structure of GluK1 ligand-binding domain (S1S2) in complex with N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl benzamide at 2.3 A resolution

Summary for 6SBT

• Entry DOI: 10.2210/pdb6sbt/pdb
• Descriptor: Glutamate receptor ionotropic, kainate 1, SULFATE ION, ~{N}-[7-imidazol-1-yl-2,3-bis(oxidanylidene)-6-(trifluoromethyl)-4~{H}-quinoxalin-1-yl]benzamide, ... (6 entities in total)
• Functional Keywords: kainate receptor ligand-binding domain, gluk1-s1s2, antagonist, membrane protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 1
• Total formula weight: 29971.00

Authors

Moellerud, S.,Frydenvang, K.,Kastrup, J.S. (deposition date: 2019-07-22, release date: 2019-10-30, Last modification date: 2024-01-24)

Primary citation

Mollerud, S.,Hansen, R.B.,Pallesen, J.,Temperini, P.,Pasini, D.,Bornholt, J.,Nielsen, B.,Mamedova, E.,Chalupnik, P.,Paternain, A.V.,Lerma, J.,Diaz-delCastillo, M.,Andreasen, J.T.,Frydenvang, K.,Kastrup, J.S.,Johansen, T.N.,Pickering, D.S.
N-(7-(1H-Imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)benzamide, a New Kainate Receptor Selective Antagonist and Analgesic: Synthesis, X-ray Crystallography, Structure-Affinity Relationships, and in Vitro and in Vivo Pharmacology.
Acs Chem Neurosci, 10:4685-4695, 2019

PubMed Abstract: Selective pharmacological tool compounds are invaluable for understanding the functions of the various ionotropic glutamate receptor subtypes. For the kainate receptors, these compounds are few. Here we have synthesized nine novel quinoxaline-2,3-diones with substitutions in the 7-position to investigate the structure-activity relationship at kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Compound exhibited the highest binding affinity across GluK1-3 while having selectivity toward kainate vs AMPA receptors. Compound potently inhibited glutamate evoked currents at homomeric GluK1 and GluK3 receptors in HEK293 cells with values of 65 and 39 nM, respectively. The binding mode of in the ligand binding domain of GluK1 was investigated by X-ray crystallography, revealing that stabilizes the receptor in an open conformation, consistent with its demonstrated antagonism. Furthermore, was tested for analgesic effects in the mouse tail flick test where it significantly increased tail flick latency at doses where 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[]-quinoxaline-7-sulfonamide (NBQX) was ineffective.

PubMed: 31622082
DOI: 10.1021/acschemneuro.9b00479

Experimental method

X-RAY DIFFRACTION (2.3 Å)