A new phenylalanine derivative acts as an antagonist at the AMPA receptor GluA2 and introduces partial domain closure: synthesis, resolution, pharmacology, and crystal structure

J Med Chem. 2011 Oct 27;54(20):7289-98. doi: 10.1021/jm200862h. Epub 2011 Oct 4.


In order to map out molecular determinants for competitive blockade of AMPA receptor subtypes, a series of 2-carboxyethylphenylalanine derivatives has been synthesized and pharmacologically characterized in vitro. One compound in this series, (RS)-3h, showed micromolar affinity for GluA1(o) and GluA2(R)(o) receptors with an approximately 4-fold preference for GluA1/2 vs GluA3/4. In TEVC electrophysiological experiments (RS)-3h competitively antagonized GluA2(Q)(i) receptors. The X-ray structure of the active enantiomer (S)-3h in complex with GluA2-S1S2J showed a domain closure around 8°. Even though the nitro and the carboxyethyl groups of (S)-3h were both anchored to Tyr702 through a water H-bond network, these interactions only induced weak subtype selectivity. In spite of the fact that (S)-3h induced a domain closure close to that observed for partial agonists, it did not produce agonist responses at GluA2 receptors under nondesensitizing conditions. 2-Carboxyethylphenylalanine derivatives provide a new synthetic scaffold for the introduction of substituents that could lead to AMPA receptor subtype-selective ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Cell Line
  • Circular Dichroism
  • Crystallography, X-Ray
  • Female
  • In Vitro Techniques
  • Models, Molecular
  • Molecular Structure
  • Oocytes / drug effects
  • Oocytes / physiology
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / chemical synthesis*
  • Phenylalanine / pharmacology
  • Protein Structure, Tertiary
  • Radioligand Assay
  • Rats
  • Receptors, AMPA / agonists
  • Receptors, AMPA / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xenopus laevis


  • 2-amino-3-(2-(2-carboxyethyl)-5-chloro-4-nitrophenyl)propionic acid
  • Receptors, AMPA
  • Phenylalanine

Associated data

  • PDB/3TZA