Discovery of the First Highly Selective Antagonist of the GluK3 Kainate Receptor Subtype
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Discovery of the First Highly Selective Antagonist of the GluK3 Kainate Receptor Subtype. / 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.
I: International Journal of Molecular Sciences, Bind 23, Nr. 15, 8797, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Discovery of the First Highly Selective Antagonist of the GluK3 Kainate Receptor Subtype
AU - Chałupnik, Paulina
AU - Vialko, Alina
AU - Pickering, Darryl S
AU - Hinkkanen, Markus
AU - Donbosco, Stephanie
AU - Møller, Thor C
AU - Jensen, Anders A
AU - Nielsen, Birgitte
AU - Bay, Yasmin
AU - Kristensen, Anders S
AU - Johansen, Tommy N
AU - Łątka, Kamil
AU - Bajda, Marek
AU - Szymańska, Ewa
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.3390/ijms23158797
DO - 10.3390/ijms23158797
M3 - Journal article
C2 - 35955932
VL - 23
JO - International Journal of Molecular Sciences (CD-ROM)
JF - International Journal of Molecular Sciences (CD-ROM)
SN - 1424-6783
IS - 15
M1 - 8797
ER -
ID: 316217458