Design and Synthesis of a Series of L-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid

Research output: Contribution to journalJournal articleResearchpeer-review

Niels Krogsgaard-Larsen, Claudia Delgar, Karina Koch, Patricia M G E Brown, Charlotte Møller, Liwei Han, Tri Hien Viet Huynh, Stinne Wessel Hansen, Birgitte Nielsen, Derek Bowie, Darryl S Pickering, Jette Sandholm Jensen Kastrup, Karla Andrea Frydenvang, Lennart Bunch

Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxy-phenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptor subtype 1 (GluK1) was attained (Ki = 4 µM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 µM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C,O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume60
Issue number1
Pages (from-to)441-457
Number of pages17
ISSN0022-2623
DOIs
Publication statusPublished - 2017

ID: 170140162