title: Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites.
abstract: In order to identify compounds selective for the GluK1 and GluK3 subtypes of kainate receptors we have designed and synthesized a series of (S)-2-amino-3-((2-carboxyethyl)phenyl)propanoic acid analogs with hydrogen bond donating and accepting substituents on the aromatic ring. Based on crystal structures of GluK1 in complex with related ligands, the compounds were designed to explore possible interactions with non-conserved residues outside the glutamate ligand binding site and challenge the water binding network. Apart from obtaining GluK1 selective antagonists one analog with a phenyl-substituted urea (compound 31) showed some preference for GluK3 over GluK1-receptors. Docking studies indicate that this preference may be attributed to contacts between the NH of the urea substituent and non-conserved Ser741 and Ser761 residues.
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, Jagtvej 162, DK-2100 Copenhagen, Denmark.
authors.forename: Niklas
authors.initials: N
authors.lastname: Sköld
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, Jagtvej 162, DK-2100 Copenhagen, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, Jagtvej 162, DK-2100 Copenhagen, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Olsen
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, Jagtvej 162, DK-2100 Copenhagen, Denmark.
authors.forename: Liwei
authors.initials: L
authors.lastname: Han
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, Jagtvej 162, DK-2100 Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Olsen
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, Jagtvej 162, DK-2100 Copenhagen, Denmark.
authors.forename: Ulf
authors.initials: U
authors.lastname: Madsen
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, Jagtvej 162, DK-2100 Copenhagen, Denmark.
authors.forename: Jesper L
authors.initials: JL
authors.lastname: Kristensen
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, Jagtvej 162, DK-2100 Copenhagen, Denmark.
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, Jagtvej 162, DK-2100 Copenhagen, Denmark. Electronic address: tnj@sund.ku.dk.
authors.forename: Tommy N
authors.initials: TN
authors.lastname: Johansen
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097808:GluK3 Kainate Receptor
chemical_list: D008024:Ligands; D010649:Phenylalanine; D018092:Kainic Acid Receptors; D000097808:GluK3 Kainate Receptor
keywords: 2-Carboxyethylphenylalanine; GluK1 antagonist; GluK3 antagonist; Glutamate receptors; Negishi reaction; SAR; Structure based design