1H-Cyclopentapyrimidine-2,4(1H,3H)-dione-Related Ionotropic Glutamate Receptors Ligands. Structure-Activity Relationships and Identification of Potent and Selective iGluR5 Modulators.

(S)-CPW399 ((S)-1) is a potent and excitotoxic AMPA receptor partial agonist. Modifying the cyclopentane ring of (S)-1, we developed two of the most potent and selective functional antagonists (5 and 7) for kainate receptor (KA-R) subunit iGluR5. Derivatives 5 and 7, with their unique pharmacological profile, may lead to a better understanding of the different roles and modes of action of iGluR1-5 subunits, paving the way for the synthesis of new potent, subunit selective iGluR5 modulators.