Domoic Acid as a Lead for the Discovery of the First Selective Ligand for Kainate Receptor Subtype 5 (GluK5)
J. Med. Chem.. 2024-08-12; 67(16): 14524-14542
DOI: 10.1021/acs.jmedchem.4c01311
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https://www.bordeaux-neurocampus.fr/12408
Buschbom-Helmke S(1), Wang P(1), Alcaide A(1), Miguez-Cabello F(2), Carta M(3),
Viotti JS(3), Nielsen B(1), Mulle C(3), Bowie D(2), Jørgensen FS(1), 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 OE, Denmark.
(2)Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill
University, H3G 0B1 Montréal, Canada.
(3)Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, University of
Bordeaux, F-33000 Bordeaux, France.
Twenty-one simplified analogues of the natural product domoic acid were
designed, synthesized, and then characterized at homomeric kainic acid (KA)
receptors (GluK1-3,5). LBG20304 displays a high affinity for homomeric GluK5
receptors (IC50 = 432 nM) with a >40-fold selectivity over homomeric GluK1-3
subtypes and ≫100-fold selectivity over native AMPA and N-methyl d-aspartate
receptors. Functional studies of LBG20304 on heteromeric GluK2/5 receptors show
no agonist or antagonist functional response at 10 μM, while a concentration of
100 μM at neuronal slices (rat) shows low agonist activity. A molecular dynamics
simulation of LBG20304, in a homology model of GluK5, suggests specific
interactions with the GluK5 receptor and an occluded ligand binding domain,
which is translated to agonist or partial agonist activity. LBG20304 is a new
compound for the study of the role and function of the KA receptors with the aim
of understanding the involvement of these receptors in health and disease.
DOI: 10.1021/acs.jmedchem.4c01311
PMID: 39133077 [Indexed for MEDLINE]