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

Stine Møllerud; Rie B Hansen; Jakob S Pallesen; Piero Temperini; Diletta Pasini; Jan Bornholdt; Birgitte Nielsen; Esmira Mamedova; Paulina Chalupnik; Ana V Paternain; Juan Lerma; Marta Diaz Del Castillo; Jesper T Andreasen; Karla Frydenvang; Jette Sandholm Kastrup; Tommy N Johansen; Darryl S Pickering

doi:10.1021/acschemneuro.9b00479

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

Stine Møllerud, Rie B Hansen, Jakob S Pallesen, Piero Temperini, Diletta Pasini, Jan Bornholdt, Birgitte Nielsen, Esmira Mamedova, Paulina Chalupnik, Ana V Paternain, Juan Lerma, Marta Diaz Del Castillo, Jesper T Andreasen, Karla Frydenvang, Jette Sandholm Kastrup, Tommy N Johansen, Darryl S Pickering

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 nine novel quinoxaline-2,3-diones with substitutions in the 7-position to investigate the structure-activity relationship at kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Compound 11 exhibited the highest binding affinity across GluK1-3 while having selectivity toward kainate vs AMPA receptors. Compound 11 potently inhibited glutamate evoked currents at homomeric GluK1 and GluK3 receptors in HEK293 cells with K_b 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 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]-quinoxaline-7-sulfonamide (NBQX) was ineffective.

Original language	English
Journal	ACS Chemical Neuroscience
Volume	10
Pages (from-to)	4685-4695
Number of pages	11
ISSN	1948-7193
DOIs	https://doi.org/10.1021/acschemneuro.9b00479
Publication status	Published - 2019

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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

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

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

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

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. doi: 10.1021/acschemneuro.9b00479

Møllerud, Stine ; Hansen, Rie B ; Pallesen, Jakob S 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. In: ACS Chemical Neuroscience. 2019 ; Vol. 10. pp. 4685-4695.

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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 nine novel quinoxaline-2,3-diones with substitutions in the 7-position to investigate the structure-activity relationship at kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Compound 11 exhibited the highest binding affinity across GluK1-3 while having selectivity toward kainate vs AMPA receptors. Compound 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 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]-quinoxaline-7-sulfonamide (NBQX) was ineffective.",

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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

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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 nine novel quinoxaline-2,3-diones with substitutions in the 7-position to investigate the structure-activity relationship at kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Compound 11 exhibited the highest binding affinity across GluK1-3 while having selectivity toward kainate vs AMPA receptors. Compound 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 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]-quinoxaline-7-sulfonamide (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 nine novel quinoxaline-2,3-diones with substitutions in the 7-position to investigate the structure-activity relationship at kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Compound 11 exhibited the highest binding affinity across GluK1-3 while having selectivity toward kainate vs AMPA receptors. Compound 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 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]-quinoxaline-7-sulfonamide (NBQX) was ineffective.

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