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

Silke Buschbom-HelmkePengfei WangAnna AlcaideFederico Miguez-CabelloMario CartaJulio S ViottiBirgitte NielsenChristophe MulleDerek BowieFlemming Steen JørgensenDarryl S PickeringLennart Bunch
Published in: Journal of medicinal chemistry (2024)
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 (IC 50 = 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.
Keyphrases
  • molecular dynamics simulations
  • public health
  • healthcare
  • molecular docking
  • oxidative stress
  • small molecule
  • health information
  • health promotion
  • structure activity relationship