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

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N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists: X-ray Crystallography, Structure-Affinity Relationships and in vitro Pharmacology. / Pallesen, Jakob Staun; Møllerud, Stine; Frydenvang, Karla Andrea; Pickering, Darryl S; Bornholt, Jan; Nielsen, Birgitte; Pasini, Diletta; Han, Liwei; Marconi, Laura; Kastrup, Jette Sandholm Jensen; Johansen, Tommy Nørskov.

In: A C S Chemical Neuroscience, Vol. 10, 20.03.2019, p. 1841-1853.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Pallesen, JS, Møllerud, S, Frydenvang, KA, Pickering, DS, Bornholt, J, Nielsen, B, Pasini, D, Han, L, Marconi, L, Kastrup, JSJ & Johansen, TN 2019, 'N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists: X-ray Crystallography, Structure-Affinity Relationships and in vitro Pharmacology', A C S Chemical Neuroscience, vol. 10, pp. 1841-1853. https://doi.org/10.1021/acschemneuro.8b00726

APA

Pallesen, J. S., Møllerud, S., Frydenvang, K. A., Pickering, D. S., Bornholt, J., Nielsen, B., ... Johansen, T. N. (2019). N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists: X-ray Crystallography, Structure-Affinity Relationships and in vitro Pharmacology. A C S Chemical Neuroscience, 10, 1841-1853. https://doi.org/10.1021/acschemneuro.8b00726

Vancouver

Pallesen JS, Møllerud S, Frydenvang KA, Pickering DS, Bornholt J, Nielsen B et al. N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists: X-ray Crystallography, Structure-Affinity Relationships and in vitro Pharmacology. A C S Chemical Neuroscience. 2019 Mar 20;10:1841-1853. https://doi.org/10.1021/acschemneuro.8b00726

Author

Pallesen, Jakob Staun ; Møllerud, Stine ; Frydenvang, Karla Andrea ; Pickering, Darryl S ; Bornholt, Jan ; Nielsen, Birgitte ; Pasini, Diletta ; Han, Liwei ; Marconi, Laura ; Kastrup, Jette Sandholm Jensen ; Johansen, Tommy Nørskov. / N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists: X-ray Crystallography, Structure-Affinity Relationships and in vitro Pharmacology. In: A C S Chemical Neuroscience. 2019 ; Vol. 10. pp. 1841-1853.

Bibtex

@article{b11d8fa853ef4e899262e635d68278ce,
title = "N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists: X-ray Crystallography, Structure-Affinity Relationships and in vitro Pharmacology",
abstract = "Among the ionotropic glutamatereceptors, the physiological role of kainate receptors is less well understood. Althoughligands with selectivity towards 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 theN1-, 6- and 7-position to investigate the structure-activity relationship (SAR) at GluK1-3and GluK5. Pharmacological characterization at native and recombinant kainate and AMPAreceptors revealed that compound 37 had a GluK3-binding affinity (Ki) of 0.142 μMand 8-fold preference for GluK3 over GluK1. Despite lower binding affinity of 22 atGluK3 (Ki = 2.91 μM) its preference for GluK3 over GluK1and 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 inan open conformation, consistent with an antagonist binding mode.",
author = "Pallesen, {Jakob Staun} and Stine M{\o}llerud and Frydenvang, {Karla Andrea} and Pickering, {Darryl S} and Jan Bornholt and Birgitte Nielsen and Diletta Pasini and Liwei Han and Laura Marconi and Kastrup, {Jette Sandholm Jensen} and Johansen, {Tommy N{\o}rskov}",
year = "2019",
month = "3",
day = "20",
doi = "10.1021/acschemneuro.8b00726",
language = "English",
volume = "10",
pages = "1841--1853",
journal = "A C S Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",

}

RIS

TY - JOUR

T1 - N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists: X-ray Crystallography, Structure-Affinity Relationships and in vitro Pharmacology

AU - Pallesen, Jakob Staun

AU - Møllerud, Stine

AU - Frydenvang, Karla Andrea

AU - Pickering, Darryl S

AU - Bornholt, Jan

AU - Nielsen, Birgitte

AU - Pasini, Diletta

AU - Han, Liwei

AU - Marconi, Laura

AU - Kastrup, Jette Sandholm Jensen

AU - Johansen, Tommy Nørskov

PY - 2019/3/20

Y1 - 2019/3/20

N2 - Among the ionotropic glutamatereceptors, the physiological role of kainate receptors is less well understood. Althoughligands with selectivity towards 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 theN1-, 6- and 7-position to investigate the structure-activity relationship (SAR) at GluK1-3and GluK5. Pharmacological characterization at native and recombinant kainate and AMPAreceptors revealed that compound 37 had a GluK3-binding affinity (Ki) of 0.142 μMand 8-fold preference for GluK3 over GluK1. Despite lower binding affinity of 22 atGluK3 (Ki = 2.91 μM) its preference for GluK3 over GluK1and 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 inan open conformation, consistent with an antagonist binding mode.

AB - Among the ionotropic glutamatereceptors, the physiological role of kainate receptors is less well understood. Althoughligands with selectivity towards 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 theN1-, 6- and 7-position to investigate the structure-activity relationship (SAR) at GluK1-3and GluK5. Pharmacological characterization at native and recombinant kainate and AMPAreceptors revealed that compound 37 had a GluK3-binding affinity (Ki) of 0.142 μMand 8-fold preference for GluK3 over GluK1. Despite lower binding affinity of 22 atGluK3 (Ki = 2.91 μM) its preference for GluK3 over GluK1and 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 inan open conformation, consistent with an antagonist binding mode.

U2 - 10.1021/acschemneuro.8b00726

DO - 10.1021/acschemneuro.8b00726

M3 - Journal article

C2 - 30620174

VL - 10

SP - 1841

EP - 1853

JO - A C S Chemical Neuroscience

JF - A C S Chemical Neuroscience

SN - 1948-7193

ER -

ID: 194250477