5m2v

Publication Abstract from PubMed

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-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 muM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 +/- 2 muM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14 degrees 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.

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.,Krogsgaard-Larsen N, Delgar CG, Koch K, Brown PM, Moller C, Han L, Huynh TH, Hansen SW, Nielsen B, Bowie D, Pickering DS, Kastrup JS, Frydenvang K, Bunch L J Med Chem. 2017 Jan 12;60(1):441-457. doi: 10.1021/acs.jmedchem.6b01516. Epub, 2016 Dec 22. PMID:28005385^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.