Discovery of the First Highly Selective Antagonist of the GluK3 Kainate Receptor Subtype

Kainate receptors belong to the family of glutamate receptors ion channels, which are responsible for the majority of rapid excitatory synaptic transmission in the central nervous system. The therapeutic potential of kainate receptors is still poorly understood, which is also due to the lack of pote...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-08, Vol.23 (15), p.8797
Main Authors: Chałupnik, Paulina, Vialko, Alina, Pickering, Darryl S, Hinkkanen, Markus, Donbosco, Stephanie, Møller, Thor C, Jensen, Anders A, Nielsen, Birgitte, Bay, Yasmin, Kristensen, Anders S, Johansen, Tommy N, Łątka, Kamil, Bajda, Marek, Szymańska, Ewa
Format: Article
Language:English
Subjects:
Affinity
Binding
Binding sites
Bipolar disorder
Central nervous system
GluK3 Kainate Receptor
glutamate receptors
Glutamic acid receptors
Glutamic acid receptors (ionotropic)
Glutamic acid receptors (metabotropic)
Ion channels
kainate receptors
Kainic acid receptors
Ligands
Molecular docking
Molecular Docking Simulation
Molecular dynamics
Pharmacology
Physiology
Protein Domains
Quinoxaline
Quinoxalines
Receptors, Kainic Acid - metabolism
Schizophrenia
Selectivity
subunit selectivity
Synaptic transmission
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Summary:Kainate receptors belong to the family of glutamate receptors ion channels, which are responsible for the majority of rapid excitatory synaptic transmission in the central nervous system. The therapeutic potential of kainate receptors is still poorly understood, which is also due to the lack of potent and subunit-selective pharmacological tools. In search of selective ligands for the GluK3 kainate receptor subtype, a series of quinoxaline-2,3-dione analogues was synthesized and pharmacologically characterized at selected recombinant ionotropic glutamate receptors. Among them, compound was found to be a competitive GluK3 antagonist with submicromolar affinity and unprecedented high binding selectivity, showing a 400-fold preference for GluK3 over other homomeric receptors GluK1, GluK2, GluK5 and GluA2. Furthermore, in functional assays performed for selected metabotropic glutamate receptor subtypes, did not show agonist or antagonist activity. The molecular determinants underlying the observed affinity profile of were analyzed using molecular docking and molecular dynamics simulations performed for individual GluK1 and GluK3 ligand-binding domains.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23158797