Domoic Acid as\na Lead for the Discovery of the First\nSelective Ligand for Kainate Receptor Subtype 5 (GluK5)

Twenty-one simplified analogues of\nthe natural product domoic acid\nwere designed, synthesized, and then characterized at homomeric kainic\nacid (KA) receptors (GluK1-3,5). <b>LBG20304</b> displays a\nhigh affinity for homomeric GluK5 receptors (IC<sub>50</sub> = 432\nnM) with a >40-fold selectivity over homomeric GluK1-3 subtypes\nand\n≫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\nor antagonist functional response at 10 μM, while a concentration\nof 100 μM at neuronal slices (rat) shows low agonist activity.\nA molecular dynamics simulation of <b>LBG20304</b>, in a homology\nmodel of GluK5, suggests specific interactions with the GluK5 receptor\nand an occluded ligand binding domain, which is translated to agonist\nor partial agonist activity. <b>LBG20304</b> is a new compound\nfor the study of the role and function of the KA receptors with the\naim of understanding the involvement of these receptors in health\nand disease.