Biomaterial Database

N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists: X-ray Crystallography, Structure-Affinity Relationships, and in Vitro Pharmacology. 2019

Jakob Pallesen, and Stine Møllerud, and Karla Frydenvang, and Darryl S Pickering, and Jan Bornholdt, and Birgitte Nielsen, and Diletta Pasini, and Liwei Han, and Laura Marconi, and Jette Sandholm Kastrup, and Tommy N Johansen

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , DK-2100 Copenhagen , Denmark.

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.

UI	MeSH Term	Description	Entries
D008958	Models, Molecular	Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.	Molecular Models,Model, Molecular,Molecular Model
D011810	Quinoxalines		Quinoxaline
D000072417	Protein Domains	Discrete protein structural units that may fold independently of the rest of the protein and have their own functions.	Peptide Domain,Protein Domain,Domain, Peptide,Domain, Protein,Domains, Peptide,Domains, Protein,Peptide Domains
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D018091	Receptors, AMPA	A class of ionotropic glutamate receptors characterized by their affinity for the agonist AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid).	AMPA Receptors,Quisqualate Receptors,AMPA Receptor,Quisqualate Receptor,Receptor, AMPA,Receptor, Quisqualate,Receptors, Quisqualate
D018092	Receptors, Kainic Acid	A class of ionotropic glutamate receptors characterized by their affinity for KAINIC ACID.	Kainate Receptors,Kainic Acid Receptors,Receptors, Kainate,Kainate Receptor,Kainic Acid Receptor,Receptor, Kainate,Receptor, Kainic Acid