TY - JOUR
T1 - Selective kainate receptor (GluK1) ligands structurally based upon1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization
AU - Venskutonyte, Raminta
AU - Butini, Stefania
AU - Coccone, Salvatore Sanna
AU - Gemma, Sandra
AU - Brindisi, Margherita
AU - Kumar, Vinod
AU - Guarino, Ergeria
AU - Maramai, Samuele
AU - Valenti, Salvatore
AU - Amir, Ahmad
AU - Valades, Elena Anton
AU - Frydenvang, Karla Andrea
AU - Kastrup, Jette Sandholm Jensen
AU - Novellino, Ettore
AU - Campiani, Giuseppe
AU - Pickering, Darryl S
PY - 2011/7/14
Y1 - 2011/7/14
N2 - 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.
AB - 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.
U2 - 10.1021/jm2004078
DO - 10.1021/jm2004078
M3 - Journal article
C2 - 21619066
VL - 54
SP - 4793
EP - 4805
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 13
ER -