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

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

12 Citations (Scopus)

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 (K_i) of 0.142 μMand 8-fold preference for GluK3 over GluK1. Despite lower binding affinity of 22 atGluK3 (K_i = 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.

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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10.1021/acschemneuro.8b00726

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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 ; 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 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

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.

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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 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.",

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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.

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