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Article

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

by
Paulina Chałupnik
1,
Alina Vialko
1,
Darryl S. Pickering
2,
Markus Hinkkanen
2,
Stephanie Donbosco
2,
Thor C. Møller
2,
Anders A. Jensen
2,
Birgitte Nielsen
2,
Yasmin Bay
2,
Anders S. Kristensen
2,
Tommy N. Johansen
2,
Kamil Łątka
3,
Marek Bajda
3 and
Ewa Szymańska
1,*
1
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College in Kraków, 30-688 Kraków, Poland
2
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
3
Department of Physicochemical Drug Analysis, Jagiellonian University Medical College in Kraków, 30-688 Kraków, Poland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(15), 8797; https://doi.org/10.3390/ijms23158797
Submission received: 12 July 2022 / Revised: 29 July 2022 / Accepted: 2 August 2022 / Published: 8 August 2022
(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation)
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Abstract

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 28 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, 28 did not show agonist or antagonist activity. The molecular determinants underlying the observed affinity profile of 28 were analyzed using molecular docking and molecular dynamics simulations performed for individual GluK1 and GluK3 ligand-binding domains.
Keywords: glutamate receptors; kainate receptors; subunit selectivity glutamate receptors; kainate receptors; subunit selectivity
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MDPI and ACS Style

Chałupnik, P.; Vialko, A.; Pickering, D.S.; Hinkkanen, M.; Donbosco, S.; Møller, T.C.; Jensen, A.A.; Nielsen, B.; Bay, Y.; Kristensen, A.S.; et al. Discovery of the First Highly Selective Antagonist of the GluK3 Kainate Receptor Subtype. Int. J. Mol. Sci. 2022, 23, 8797. https://doi.org/10.3390/ijms23158797

AMA Style

Chałupnik P, Vialko A, Pickering DS, Hinkkanen M, Donbosco S, Møller TC, Jensen AA, Nielsen B, Bay Y, Kristensen AS, et al. Discovery of the First Highly Selective Antagonist of the GluK3 Kainate Receptor Subtype. International Journal of Molecular Sciences. 2022; 23(15):8797. https://doi.org/10.3390/ijms23158797

Chicago/Turabian Style

Chałupnik, Paulina, Alina Vialko, Darryl S. Pickering, Markus Hinkkanen, Stephanie Donbosco, Thor C. Møller, Anders A. Jensen, Birgitte Nielsen, Yasmin Bay, Anders S. Kristensen, and et al. 2022. "Discovery of the First Highly Selective Antagonist of the GluK3 Kainate Receptor Subtype" International Journal of Molecular Sciences 23, no. 15: 8797. https://doi.org/10.3390/ijms23158797

APA Style

Chałupnik, P., Vialko, A., Pickering, D. S., Hinkkanen, M., Donbosco, S., Møller, T. C., Jensen, A. A., Nielsen, B., Bay, Y., Kristensen, A. S., Johansen, T. N., Łątka, K., Bajda, M., & Szymańska, E. (2022). Discovery of the First Highly Selective Antagonist of the GluK3 Kainate Receptor Subtype. International Journal of Molecular Sciences, 23(15), 8797. https://doi.org/10.3390/ijms23158797

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