Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors

Research output: Contribution to journalArticle

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.

Details

Authors
  • Ewa Szymanska
  • Karla Andrea Frydenvang
  • Darryl S Pickering
  • Christian Krintel
  • Anne-Birgitte Nielsen
  • Ayesheh Kooshki
  • Linda Grønborg Zachariassen
  • Lars Olsen
  • Jette Sandholm Jensen Kastrup
  • Tommy Nørskov Johansen
External organisations
  • University of Copenhagen
Original languageEnglish
Pages (from-to)448-461
JournalJournal of Medicinal Chemistry
Volume59
Issue number1
Publication statusPublished - 2016
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes