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

Christian B. M. Poulie, Younes Larsen, Cindie Leteneur, Gaël Barthet, Walden E. Bjørn-Yoshimoto, Fanny Malhaire, Birgitte Nielsen, Jean-Phillippe Pin, Christophe Mulle, Darryl S. Pickering, Lennart Bunch
ACS Chem. Neurosci.. 2022-04-27; 13(10): 1580-1587
DOI: 10.1021/acschemneuro.2c00162

Read on PubMed

Poulie CBM(1), Larsen Y(1), Leteneur C(2), Barthet G(2), Bjørn-Yoshimoto WE(1), Malhaire F(3), Nielsen B(1), Pin JP(3), Mulle C(2), Pickering DS(1), Bunch L(1).

Author information:
(1)Department of Drug Design and Pharmacology, Faculty of Health and Medical
Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
(2)Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, Université de
Bordeaux, CNRS, F-33000 Bordeaux, France.
(3)IGF, INSERM, Université de Montpellier, CNRS, F-34094 Montpellier, France.

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


Know more about