Kainate receptors (KAR) are ligand-gated ion channels activated upon binding of the neurotransmitter glutamate.1 They are highly expressed in the central nervous system and there is evidence that these receptors play a role in stroke, epilepsy and pain.2 Compared to other glutamate receptors, progress in the understanding of their function has lagged behind, due mainly to the lack of specific antagonists.1 KARs are tetramers composed of the different subunits GluK1-GluK53 and at present, some selective inhibitors for the subunit GluK1 are available. However, for the most abundant GluK2 subunit, no selective inhibitors have been reported in literature. The aim of my project is to develop specific antagonists for the GluK2 subunit with the natural lignin (-)-arctigenin as the lead compound. Arctigenin was found to bind to KARs4 and our molecular modelling studies suggest that the lactone oxygens and the hydroxyl-group are important features for the binding to GluK2 (Figure 1). SAR studies are being carried out to confirm these findings and develop GluK2 inhibitors. Therefore, analogues of arctigenin have been prepared (Figure 2). The first target compounds include analogues with different substitution on the aromatic rings (e.g. 1), the unnatural (+)-enantiomer of arctigenin 2, analogues with varying substitution at the lactone (e.g. 3) and derivatives with changes at the core ring (e.g. 4). The molecular design and synthetic studies towards these target compounds and preliminary SAR will be described. 1Jane, D. E.; Lodge, D.; Collingridge, G. L. Neuropharmacology 2009, 56, 90 2Vincent, P.; Mulle, C. Neuroscience 2009, 158, 309 3Mayer, M. L. Nature 2006, 440, 456 4Jang, Y. P. et. al. J. Neurosci. Res. 2002, 68, 233

Natural product lead for the design and synthesis of selective inhibitors of kainate receptors

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.