title: Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors.
abstract: A series of racemic aryl-substituted phenylalanines was synthesized and evaluated in vitro at recombinant rat GluA1-3, at GluK1-3, and at native AMPA receptors. The individual enantiomers of two target compounds, (RS)-2-amino-3-(3,4-dichloro-5-(5-hydroxypyridin-3-yl)phenyl)propanoic acid 37 and (RS)-2-amino-3-(3'-hydroxybiphenyl-3-yl)propanoic acid 38, were characterized. (S)-37 and (R)-38 were identified as the only biologically active isomers, both being antagonists at GluA2 receptors with Kb of 1.80 and 3.90 μM, respectively. To address this difference in enantiopharmacology, not previously seen for amino acid-based AMPA receptor antagonists, X-ray crystal structures of both eutomers in complex with the GluA2 ligand binding domain were solved. The cocrystal structures of (S)-37 and (R)-38 showed similar interactions of the amino acid parts but unexpected and different orientations and interactions of the biaromatic parts of the ligands inside the binding site, with (R)-38 having a binding mode not previously identified for amino acid-based antagonists.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Ewa
authors.initials: E
authors.lastname: Szymanska
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, 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 , 2100 Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Krintel
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, 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 , 2100 Copenhagen, Denmark.
authors.forename: Ayesheh
authors.initials: A
authors.lastname: Kooshki
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Linda G
authors.initials: LG
authors.lastname: Zachariassen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Olsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Jette S
authors.initials: JS
authors.lastname: Kastrup
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Tommy N
authors.initials: TN
authors.lastname: Johansen
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000187:drug effects; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D018691:Excitatory Amino Acid Antagonists; D010649:Phenylalanine; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D011994:Recombinant Proteins; C104722:glutamate receptor ionotropic, AMPA 2