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

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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 languageEnglish
JournalACS Chemical Neuroscience
Issue number10
Pages (from-to)1580–1587
Publication statusPublished - 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).

    Research areas

  • amino acid, CNS, GluK3, glutamate receptors, kainate

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