Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors

The natural product willardiine (8) is an AMPA receptor agonist while 5-iodowillardiine (10) is a selective kainate receptor agonist. In an attempt to produce antagonists of kainate and AMPA receptors analogues of willardiine with substituents at the N-3 position of the uracil ring were synthesized. The N-3-4-carboxybenzyl substituted analogue (38c) was found to be equipotent at AMPA and GLU(K5)-containing kainate receptors in the neonatal rat spinal cord. The N-3-2-carboxybenzyl substituted analogue (38a) proved to be a potent and selective GLU(K5) subunit containing kainate receptor antagonist when tested on native rat and human recombinant AMPA and kainate receptor subtypes. The GLU(K5) kainate receptor antagonist activity was found to reside in the S enantiomer (44a) whereas the R enantiomer (44b) was almost inactive. 5-Iodo substitution of the uracil ring of 44a gave 45, which was found to have enhanced potency and selectivity for GLU(K5).