(S)-2-Mercaptohistidine: A First Selective Orthosteric GluK3 Antagonist

Christian B.M. Poulie; Younes Larsen; Cindie Leteneur; Gael Barthet; Walden E. Bjorn-Yoshimoto; Fanny Malhaire; Birgitte Nielsen; Jean Phillippe Pin; Christophe Mulle; Darryl S. Pickering; Lennart Bunch

doi:10.1021/acschemneuro.2c00162

(S)-2-Mercaptohistidine: A First Selective Orthosteric GluK3 Antagonist

Christian B.M. Poulie^*, Younes Larsen, Cindie Leteneur, Gael Barthet, Walden E. Bjorn-Yoshimoto, Fanny Malhaire, Birgitte Nielsen, Jean Phillippe Pin, Christophe Mulle, Darryl S. Pickering, Lennart Bunch

^*Corresponding author for this work

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

3 Citations (Scopus)

Abstract

The development of tool compounds for the ionotropic glutamate receptors (iGluRs) remains an important research objective, as these are essential for the study and understanding of the roles of these receptors in health and disease. Herein, we report on the pharmacological characterization of (S)-2-hydroxyhistidine (2a) and (S)-2-mercaptohistidine (2b) as mediators of glutamatergic neurotransmission. While 2a displayed negligible binding affinity or activity at all glutamate receptors and transporters investigated, 2b displayed selectivity for homomeric GluK3 with binding affinities in the low micromolar range (Ki = 6.42 ± 0.74 μM). The iGluR subtype selectivity ratio for 2b was calculated at 30-fold for GluK1/GluK3, GluA3/GluK3, and GluA4/GluK3 and >100-fold for GluK2/GluK3, GluA1/GluK3, and GluA2/GluK3. Unexpectedly, functional characterization of 2b revealed that the compound is an antagonist (Kb = 7.6 μM) at homomeric GluK3 receptors while exhibiting only weak agonist activity at GluA2 (EC50 = 3.25 ± 0.55 mM). The functional properties of 2b were explored further in electrophysiological recordings of mouse hippocampal neurons.

Original language	English
Journal	ACS Chemical Neuroscience
Volume	13
Issue number	10
Pages (from-to)	1580–1587
ISSN	1948-7193
DOIs	https://doi.org/10.1021/acschemneuro.2c00162
Publication status	Published - 2022

Bibliographical note

Funding Information:
The authors thank the University of Copenhagen for the financial support. Anders A. Jensen is acknowledged for the use of the EAAT1–3-HEK293 cells. J.-P.P. acknowledges the Arpège platform of the Institut de Génomique Fonctionnelle for providing facilities and technical support and PerkinElmer Cisbio for providing reagents. J.-P.P. was supported by the CNRS, INSERM and the Fondation Recherche Médicale (FRM) (Equipe DEQ20170336747).

Keywords

amino acid
CNS
GluK3
glutamate receptors
kainate

Access to Document

10.1021/acschemneuro.2c00162

Cite this

(S)-2-Mercaptohistidine : A First Selective Orthosteric GluK3 Antagonist. / Poulie, Christian B.M.; Larsen, Younes; Leteneur, Cindie; Barthet, Gael; Bjorn-Yoshimoto, Walden E.; Malhaire, Fanny; Nielsen, Birgitte; Pin, Jean Phillippe; Mulle, Christophe; Pickering, Darryl S.; Bunch, Lennart.

In: ACS Chemical Neuroscience, Vol. 13, No. 10, 2022, p. 1580–1587.

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

Poulie, Christian B.M. ; Larsen, Younes ; Leteneur, Cindie ; Barthet, Gael ; Bjorn-Yoshimoto, Walden E. ; Malhaire, Fanny ; Nielsen, Birgitte ; Pin, Jean Phillippe ; Mulle, Christophe ; Pickering, Darryl S. ; Bunch, Lennart. / (S)-2-Mercaptohistidine : A First Selective Orthosteric GluK3 Antagonist. In: ACS Chemical Neuroscience. 2022 ; Vol. 13, No. 10. pp. 1580–1587.

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abstract = "The development of tool compounds for the ionotropic glutamate receptors (iGluRs) remains an important research objective, as these are essential for the study and understanding of the roles of these receptors in health and disease. Herein, we report on the pharmacological characterization of (S)-2-hydroxyhistidine (2a) and (S)-2-mercaptohistidine (2b) as mediators of glutamatergic neurotransmission. While 2a displayed negligible binding affinity or activity at all glutamate receptors and transporters investigated, 2b displayed selectivity for homomeric GluK3 with binding affinities in the low micromolar range (Ki = 6.42 ± 0.74 μM). The iGluR subtype selectivity ratio for 2b was calculated at 30-fold for GluK1/GluK3, GluA3/GluK3, and GluA4/GluK3 and >100-fold for GluK2/GluK3, GluA1/GluK3, and GluA2/GluK3. Unexpectedly, functional characterization of 2b revealed that the compound is an antagonist (Kb = 7.6 μM) at homomeric GluK3 receptors while exhibiting only weak agonist activity at GluA2 (EC50 = 3.25 ± 0.55 mM). The functional properties of 2b were explored further in electrophysiological recordings of mouse hippocampal neurons. ",

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note = "Funding Information: The authors thank the University of Copenhagen for the financial support. Anders A. Jensen is acknowledged for the use of the EAAT1–3-HEK293 cells. J.-P.P. acknowledges the Arp{\`e}ge platform of the Institut de G{\'e}nomique Fonctionnelle for providing facilities and technical support and PerkinElmer Cisbio for providing reagents. J.-P.P. was supported by the CNRS, INSERM and the Fondation Recherche M{\'e}dicale (FRM) (Equipe DEQ20170336747). ",

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T2 - A First Selective Orthosteric GluK3 Antagonist

AU - Poulie, Christian B.M.

AU - Larsen, Younes

AU - Leteneur, Cindie

AU - Barthet, Gael

AU - Bjorn-Yoshimoto, Walden E.

AU - Malhaire, Fanny

AU - Nielsen, Birgitte

AU - Pin, Jean Phillippe

AU - Mulle, Christophe

AU - Pickering, Darryl S.

AU - Bunch, Lennart

N1 - Funding Information: The authors thank the University of Copenhagen for the financial support. Anders A. Jensen is acknowledged for the use of the EAAT1–3-HEK293 cells. J.-P.P. acknowledges the Arpège platform of the Institut de Génomique Fonctionnelle for providing facilities and technical support and PerkinElmer Cisbio for providing reagents. J.-P.P. was supported by the CNRS, INSERM and the Fondation Recherche Médicale (FRM) (Equipe DEQ20170336747).

PY - 2022

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N2 - The development of tool compounds for the ionotropic glutamate receptors (iGluRs) remains an important research objective, as these are essential for the study and understanding of the roles of these receptors in health and disease. Herein, we report on the pharmacological characterization of (S)-2-hydroxyhistidine (2a) and (S)-2-mercaptohistidine (2b) as mediators of glutamatergic neurotransmission. While 2a displayed negligible binding affinity or activity at all glutamate receptors and transporters investigated, 2b displayed selectivity for homomeric GluK3 with binding affinities in the low micromolar range (Ki = 6.42 ± 0.74 μM). The iGluR subtype selectivity ratio for 2b was calculated at 30-fold for GluK1/GluK3, GluA3/GluK3, and GluA4/GluK3 and >100-fold for GluK2/GluK3, GluA1/GluK3, and GluA2/GluK3. Unexpectedly, functional characterization of 2b revealed that the compound is an antagonist (Kb = 7.6 μM) at homomeric GluK3 receptors while exhibiting only weak agonist activity at GluA2 (EC50 = 3.25 ± 0.55 mM). The functional properties of 2b were explored further in electrophysiological recordings of mouse hippocampal neurons.

AB - The development of tool compounds for the ionotropic glutamate receptors (iGluRs) remains an important research objective, as these are essential for the study and understanding of the roles of these receptors in health and disease. Herein, we report on the pharmacological characterization of (S)-2-hydroxyhistidine (2a) and (S)-2-mercaptohistidine (2b) as mediators of glutamatergic neurotransmission. While 2a displayed negligible binding affinity or activity at all glutamate receptors and transporters investigated, 2b displayed selectivity for homomeric GluK3 with binding affinities in the low micromolar range (Ki = 6.42 ± 0.74 μM). The iGluR subtype selectivity ratio for 2b was calculated at 30-fold for GluK1/GluK3, GluA3/GluK3, and GluA4/GluK3 and >100-fold for GluK2/GluK3, GluA1/GluK3, and GluA2/GluK3. Unexpectedly, functional characterization of 2b revealed that the compound is an antagonist (Kb = 7.6 μM) at homomeric GluK3 receptors while exhibiting only weak agonist activity at GluA2 (EC50 = 3.25 ± 0.55 mM). The functional properties of 2b were explored further in electrophysiological recordings of mouse hippocampal neurons.

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KW - CNS

KW - GluK3

KW - glutamate receptors

KW - kainate

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VL - 13

SP - 1580

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JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

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