N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)benzamide - a new kainate receptor selective antagonist and analgesic: Synthesis, X-ray crystallography, structure-affinity relationships, in vitro and in vivo pharmacology

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

Standard

N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)benzamide - a new kainate receptor selective antagonist and analgesic : Synthesis, X-ray crystallography, structure-affinity relationships, in vitro and in vivo pharmacology. / Møllerud, Stine; Hansen, Rie B; Pallesen, Jakob S; Temperini, Piero; Pasini, Diletta; Bornholdt, Jan; Nielsen, Birgitte; Mamedova, Esmira; Chalupnik, Paulina; Paternain, Ana V; Lerma, Juan; Del Castillo, Marta Diaz; Andreasen, Jesper T; Frydenvang, Karla; Kastrup, Jette Sandholm; Johansen, Tommy N; Pickering, Darryl S.

In: ACS Chemical Neuroscience, Vol. 10, 2019, p. 4685-4695.

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

Harvard

Møllerud, S, Hansen, RB, Pallesen, JS, Temperini, P, Pasini, D, Bornholdt, J, Nielsen, B, Mamedova, E, Chalupnik, P, Paternain, AV, Lerma, J, Del Castillo, MD, Andreasen, JT, Frydenvang, K, Kastrup, JS, Johansen, TN & Pickering, DS 2019, 'N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)benzamide - a new kainate receptor selective antagonist and analgesic: Synthesis, X-ray crystallography, structure-affinity relationships, in vitro and in vivo pharmacology', ACS Chemical Neuroscience, vol. 10, pp. 4685-4695. https://doi.org/10.1021/acschemneuro.9b00479

APA

Møllerud, S., Hansen, R. B., Pallesen, J. S., Temperini, P., Pasini, D., Bornholdt, J., Nielsen, B., Mamedova, E., Chalupnik, P., Paternain, A. V., Lerma, J., Del Castillo, M. D., Andreasen, J. T., Frydenvang, K., Kastrup, J. S., Johansen, T. N., & Pickering, D. S. (2019). N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)benzamide - a new kainate receptor selective antagonist and analgesic: Synthesis, X-ray crystallography, structure-affinity relationships, in vitro and in vivo pharmacology. ACS Chemical Neuroscience, 10, 4685-4695. https://doi.org/10.1021/acschemneuro.9b00479

Vancouver

Møllerud S, Hansen RB, Pallesen JS, Temperini P, Pasini D, Bornholdt J et al. N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)benzamide - a new kainate receptor selective antagonist and analgesic: Synthesis, X-ray crystallography, structure-affinity relationships, in vitro and in vivo pharmacology. ACS Chemical Neuroscience. 2019;10:4685-4695. https://doi.org/10.1021/acschemneuro.9b00479

Author

Møllerud, Stine ; Hansen, Rie B ; Pallesen, Jakob S ; Temperini, Piero ; Pasini, Diletta ; Bornholdt, Jan ; Nielsen, Birgitte ; Mamedova, Esmira ; Chalupnik, Paulina ; Paternain, Ana V ; Lerma, Juan ; Del Castillo, Marta Diaz ; Andreasen, Jesper T ; Frydenvang, Karla ; Kastrup, Jette Sandholm ; Johansen, Tommy N ; Pickering, Darryl S. / N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)benzamide - a new kainate receptor selective antagonist and analgesic : Synthesis, X-ray crystallography, structure-affinity relationships, in vitro and in vivo pharmacology. In: ACS Chemical Neuroscience. 2019 ; Vol. 10. pp. 4685-4695.

Bibtex

@article{c044742c9663435eabaa40c68afcfdec,
title = "N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)benzamide - a new kainate receptor selective antagonist and analgesic: Synthesis, X-ray crystallography, structure-affinity relationships, in vitro and in vivo pharmacology",
abstract = "Selective pharmacological tool compounds are invaluable for understanding the functions of the various ionotropic glutamate receptor subtypes. For the kainate receptors these compounds are few. Here we have synthesized 9 novel quinoxaline-2,3-diones with substitutions in the 7-position to investigate the structure-activity relationship at kainate and AMPA receptors. Compound 11 exhibited the highest binding affinity across GluK1-3 while having a 73-fold selectivity towards kainate vs. AMPA receptors. 11 potently inhibited glutamate evoked currents at homomeric GluK1 and GluK3 receptors in HEK293 cells with Kb values of 65 and 39 nM, respectively. The binding mode of 11 in the ligand binding domain of GluK1 was investigated by X-ray crystallography, revealing that 11 stabilizes the receptor in an open conformation, consistent with its demonstrated antagonism. Furthermore, 11 was tested for analgesic effects in the mouse tail flick test where it significantly increased tail flick latency at doses where NBQX was ineffective.",
author = "Stine M{\o}llerud and Hansen, {Rie B} and Pallesen, {Jakob S} and Piero Temperini and Diletta Pasini and Jan Bornholdt and Birgitte Nielsen and Esmira Mamedova and Paulina Chalupnik and Paternain, {Ana V} and Juan Lerma and {Del Castillo}, {Marta Diaz} and Andreasen, {Jesper T} and Karla Frydenvang and Kastrup, {Jette Sandholm} and Johansen, {Tommy N} and Pickering, {Darryl S}",
year = "2019",
doi = "10.1021/acschemneuro.9b00479",
language = "English",
volume = "10",
pages = "4685--4695",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",

}

RIS

TY - JOUR

T1 - N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)benzamide - a new kainate receptor selective antagonist and analgesic

T2 - Synthesis, X-ray crystallography, structure-affinity relationships, in vitro and in vivo pharmacology

AU - Møllerud, Stine

AU - Hansen, Rie B

AU - Pallesen, Jakob S

AU - Temperini, Piero

AU - Pasini, Diletta

AU - Bornholdt, Jan

AU - Nielsen, Birgitte

AU - Mamedova, Esmira

AU - Chalupnik, Paulina

AU - Paternain, Ana V

AU - Lerma, Juan

AU - Del Castillo, Marta Diaz

AU - Andreasen, Jesper T

AU - Frydenvang, Karla

AU - Kastrup, Jette Sandholm

AU - Johansen, Tommy N

AU - Pickering, Darryl S

PY - 2019

Y1 - 2019

N2 - Selective pharmacological tool compounds are invaluable for understanding the functions of the various ionotropic glutamate receptor subtypes. For the kainate receptors these compounds are few. Here we have synthesized 9 novel quinoxaline-2,3-diones with substitutions in the 7-position to investigate the structure-activity relationship at kainate and AMPA receptors. Compound 11 exhibited the highest binding affinity across GluK1-3 while having a 73-fold selectivity towards kainate vs. AMPA receptors. 11 potently inhibited glutamate evoked currents at homomeric GluK1 and GluK3 receptors in HEK293 cells with Kb values of 65 and 39 nM, respectively. The binding mode of 11 in the ligand binding domain of GluK1 was investigated by X-ray crystallography, revealing that 11 stabilizes the receptor in an open conformation, consistent with its demonstrated antagonism. Furthermore, 11 was tested for analgesic effects in the mouse tail flick test where it significantly increased tail flick latency at doses where NBQX was ineffective.

AB - Selective pharmacological tool compounds are invaluable for understanding the functions of the various ionotropic glutamate receptor subtypes. For the kainate receptors these compounds are few. Here we have synthesized 9 novel quinoxaline-2,3-diones with substitutions in the 7-position to investigate the structure-activity relationship at kainate and AMPA receptors. Compound 11 exhibited the highest binding affinity across GluK1-3 while having a 73-fold selectivity towards kainate vs. AMPA receptors. 11 potently inhibited glutamate evoked currents at homomeric GluK1 and GluK3 receptors in HEK293 cells with Kb values of 65 and 39 nM, respectively. The binding mode of 11 in the ligand binding domain of GluK1 was investigated by X-ray crystallography, revealing that 11 stabilizes the receptor in an open conformation, consistent with its demonstrated antagonism. Furthermore, 11 was tested for analgesic effects in the mouse tail flick test where it significantly increased tail flick latency at doses where NBQX was ineffective.

U2 - 10.1021/acschemneuro.9b00479

DO - 10.1021/acschemneuro.9b00479

M3 - Journal article

C2 - 31622082

VL - 10

SP - 4685

EP - 4695

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

ER -

ID: 229279705