title: Design, synthesis and structure-activity relationships of novel phenylalanine-based amino acids as kainate receptors ligands.
abstract: A new series of carboxyaryl-substituted phenylalanines was designed, synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors as well as at cloned homomeric kainate receptors GluK1-GluK3. Among them, six compounds bound to GluK1 receptor subtypes with reasonable affinity (Kivalues in the range of 4.9-7.5μM). A structure-activity relationship (SAR) for the obtained series, focused mainly on the pharmacological effect of structural modifications in the 4- and 5-position of the phenylalanine ring, was established. To illustrate the results, molecular docking of the synthesized series to the X-ray structure of GluK1 ligand binding core was performed. The influence of individual substituents at the phenylalanine ring for both the affinity and selectivity at AMPA, GluK1 and GluK3 receptors was analyzed, giving directions for future studies.
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address: ewa.szymanska@uj.edu.pl.
authors.forename: Ewa
authors.initials: E
authors.lastname: Szymańska
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Chałupnik
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Szczepańska
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK 2100 Copenhagen Ø, Denmark.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuñado Moral
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK 2100 Copenhagen Ø, Denmark.
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK 2100 Copenhagen Ø, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK 2100 Copenhagen Ø, Denmark.
authors.forename: Tommy N
authors.initials: TN
authors.lastname: Johansen
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D008024:Ligands; D062105:Molecular Docking Simulation; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / 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: GluK1; GluK3; Ionotropic glutamate receptors; Kainate receptors; Phenylalanine