Domoic Acid as a Lead for the Discovery of the First Selective Ligand for Kainate Receptor Subtype 5 (GluK5)

Silke Buschbom-Helmke, Pengfei Wang, Anna Alcaide, Federico Miguez-Cabello, Mario Carta, Julio S. Viotti, Birgitte Nielsen, Christophe Mulle, Derek Bowie, Flemming Steen Jørgensen, Darryl S. Pickering, Lennart Bunch*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume67
Issue number16
Pages (from-to)14524–14542
ISSN0022-2623
DOIs
Publication statusPublished - 2024

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© 2024 American Chemical Society.

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