title: Selective kainate receptor (GluK1) ligands structurally based upon 1H-cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization.
abstract: 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 cocrystallized 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.
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Raminta
authors: R
authors: Venskutonyte
authors: Stefania
authors: S
authors: Butini
authors: Salvatore Sanna
authors: SS
authors: Coccone
authors: Sandra
authors: S
authors: Gemma
authors: Margherita
authors: M
authors: Brindisi
authors: Vinod
authors: V
authors: Kumar
authors: Egeria
authors: E
authors: Guarino
authors: Samuele
authors: S
authors: Maramai
authors: Salvatore
authors: S
authors: Valenti
authors: Ahmad
authors: A
authors: Amir
authors: Elena Antón
authors: EA
authors: Valadés
authors: Karla
authors: K
authors: Frydenvang
authors: Jette S
authors: JS
authors: Kastrup
authors: Ettore
authors: E
authors: Novellino
authors: Giuseppe
authors: G
authors: Campiani
authors: Darryl S
authors: DS
authors: Pickering