title: Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid.
abstract: Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Krogsgaard-Larsen
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Storgaard
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Møller
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Demmer
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Hansen
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Liwei
authors.initials: L
authors.lastname: Han
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Rune N
authors.initials: RN
authors.lastname: Monrad
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tapken
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Jette S
authors.initials: JS
authors.lastname: Kastrup
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.affiliation: †Chemical Neuroscience Group, ‡Biostructural Research Group, §Medicinal Chemistry Group, ∥Molecular, Cellular Pharmacology Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
mesh_terms: D018360:Crystallography, X-Ray; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D011759:Pyrrolidines / Q000494:pharmacology*; D058468:Receptors, Ionotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D018691:Excitatory Amino Acid Antagonists; D011759:Pyrrolidines; D058468:Receptors, Ionotropic Glutamate