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

Jakob Staun Pallesen; Stine Møllerud; Karla Andrea Frydenvang; Darryl S Pickering; Jan Bornholt; Birgitte Nielsen; Diletta Pasini; Liwei Han; Laura Marconi; Jette Sandholm Jensen Kastrup; Tommy Nørskov Johansen

doi:10.1021/acschemneuro.8b00726

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

Jakob Staun Pallesen, Stine Møllerud, Karla Andrea Frydenvang, Darryl S Pickering, Jan Bornholt, Birgitte Nielsen, Diletta Pasini, Liwei Han, Laura Marconi, Jette Sandholm Jensen Kastrup, Tommy Nørskov Johansen

4 Citations (Scopus)

Abstract

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 (K _i ) of 0.142 μM and 8-fold preference for GluK3 over GluK1. Despite lower binding affinity of 22 at GluK3 (K _i = 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.

Original language	English
Journal	A C S Chemical Neuroscience
Volume	10
Pages (from-to)	1841-1853
Number of pages	13
ISSN	1948-7193
DOIs	https://doi.org/10.1021/acschemneuro.8b00726
Publication status	Published - 20 Mar 2019

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Pallesen, J. S., Møllerud, S., Frydenvang, K. A., Pickering, D. S., Bornholt, J., Nielsen, B., Pasini, D., Han, L., Marconi, L., Kastrup, J. S. J., & 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

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 et al.

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

Research output: Contribution to journal › Journal article › Research › peer-review

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

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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 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 (K i ) of 0.142 μM and 8-fold preference for GluK3 over GluK1. Despite lower binding affinity of 22 at GluK3 (K i = 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. ",

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}",

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doi = "10.1021/acschemneuro.8b00726",

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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 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 (K i ) of 0.142 μM and 8-fold preference for GluK3 over GluK1. Despite lower binding affinity of 22 at GluK3 (K i = 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.

AB - 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 (K i ) of 0.142 μM and 8-fold preference for GluK3 over GluK1. Despite lower binding affinity of 22 at GluK3 (K i = 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.

U2 - 10.1021/acschemneuro.8b00726

DO - 10.1021/acschemneuro.8b00726

M3 - Journal article

C2 - 30620174

SN - 1948-7193

VL - 10

SP - 1841

EP - 1853

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

ER -

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

Abstract

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