Domoic Acid as a Lead for the Discovery of the First Selective Ligand for Kainate Receptor Subtype 5 (GluK5)
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). <b>LBG20304</b> displays a high affinity for homomeric GluK5 receptors (IC<sub>50</sub> = 432 nM) with a >40-fold selectivity over homomeric GluK1-3 subtypes and ≫100-fold selectivity over native AMPA and <i>N</i>-methyl d-aspartate receptors. Functional studies of <b>LBG20304</b> 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 <b>LBG20304</b>, 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. <b>LBG20304</b> 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.
Authors
- Derek Bowie (ORCID: https://orcid.org/0000-0001-9491-8768)
- Birgitte Nielsen (ORCID: https://orcid.org/0000-0002-1715-6269)
- Flemming Steen Jørgensen (ORCID: https://orcid.org/0000-0001-8040-2998)
- Julio Viotti (ORCID: https://orcid.org/0000-0003-3631-6456)
- Lennart Bunch (ORCID: https://orcid.org/0000-0002-0180-4639)
- Silke Buschbom-Helmke
- Federico Míguez‐Cabello (ORCID: https://orcid.org/0000-0002-6154-1922)
- Anna Alcaide
- Christophe Mulle (ORCID: https://orcid.org/0000-0003-2709-6615)
- Darryl S. Pickering (ORCID: https://orcid.org/0000-0001-8687-6094)
- Pengfei Wang (ORCID: https://orcid.org/0000-0002-9081-3683)
- Mario Carta (ORCID: https://orcid.org/0000-0003-1225-2742)
Institutions
- University of Copenhagen (DK)
- Centre National de la Recherche Scientifique (FR)
- Université de Bordeaux (FR)
- Institut Interdisciplinaire de Neuroscience (FR)
- McGill University (CA)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-08-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01311
- Primary Topic
- Carbohydrate Chemistry and Synthesis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- McGill University
- Faculty of Medicine, McGill University
- Agence Nationale de la Recherche
- Lundbeckfonden
- Centre National de la Recherche Scientifique
- Université de Bordeaux
- Faculty of Health and Medical Sciences, University of Western Australia
- Det Sundhedsvidenskabelige Fakultet, Københavns Universitet