Selective kainate receptor (GluK1) ligands structurally based upon1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization

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Raminta Venskutonyte, Stefania Butini, Salvatore Sanna Coccone, Sandra Gemma, Margherita Brindisi, Vinod Kumar, Ergeria Guarino, Samuele Maramai, Salvatore Valenti, Ahmad Amir, Elena Anton Valades, Karla Andrea Frydenvang, Jette Sandholm Jensen Kastrup, Ettore Novellino, Giuseppe Campiani, Darryl S Pickering

The physiological function of kainate receptors (GluK1- GluK5) in the central nervous system is not fully understood yet. With the aim of developing potent and selective GluK1 ligands, we have synthesized a series of new thiophene-based GluK1 agonists (6a-c) and antagonists (7a-d). Pharmacological evaluation revealed that they are selective for the GluK1 subunit, with 7b being the most subtype-selective ligand reported to date (GluK1 vs GluK3). The antagonist 7a was crystallized with the GluK1 ligand binding domain, and an X-ray crystallographic analysis revealed the largest flexibility in GluK1 ligand binding domain opening upon binding of a ligand seen to date. The results provide new insights into the molecular mechanism of GluK1 receptor ligand binding and pave the way to the development of new tool compounds for studying kainate receptor function.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume54
Issue number13
Pages (from-to)4793-4805
ISSN0022-2623
DOIs
Publication statusPublished - 14 Jul 2011

ID: 33603380