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). 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.