title: 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.
abstract: 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 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.
authors.forename: Niels
authors.initials: N
authors.lastname: Krogsgaard-Larsen
authors.forename: Claudia G
authors.initials: CG
authors.lastname: Delgar
authors.forename: Karina
authors.initials: K
authors.lastname: Koch
authors.affiliation: Bowie Lab, Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University , Montreal, Quebec H3G 0B1, Canada.
authors.forename: Patricia M G E
authors.initials: PM
authors.lastname: Brown
authors.forename: Charlotte
authors.initials: C
authors.lastname: Møller
authors.forename: Liwei
authors.initials: L
authors.lastname: Han
authors.forename: Tri H V
authors.initials: TH
authors.lastname: Huynh
authors.forename: Stinne W
authors.initials: SW
authors.lastname: Hansen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.affiliation: Bowie Lab, Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University , Montreal, Quebec H3G 0B1, Canada.
authors.forename: Derek
authors.initials: D
authors.lastname: Bowie
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
authors.forename: Jette Sandholm
authors.initials: JS
authors.lastname: Kastrup
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.forename: Lennart
authors.identifier: 0000-0002-0180-4639
authors.initials: L
authors.lastname: Bunch
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D020128:Inhibitory Concentration 50; D011392:Proline / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D058468:Receptors, Ionotropic Glutamate / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D011392:Proline; D011759:Pyrrolidines; D058468:Receptors, Ionotropic Glutamate; D018092:Kainic Acid Receptors