Chemoenzymatic synthesis of new 2,4-syn-functionalized (S)-glutamate analogues and structure-activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters

J Med Chem. 2013 Feb 28;56(4):1614-28. doi: 10.1021/jm301433m. Epub 2013 Feb 15.

Abstract

In the mammalian central nervous system, (S)-glutamate (Glu) is released from the presynaptic neuron where it activates a plethora of pre- and postsynaptic Glu receptors. The fast acting ionotropic Glu receptors (iGluRs) are ligand gated ion channels and are believed to be involved in a vast number of neurological functions such as memory and learning, synaptic plasticity, and motor function. The synthesis of 14 enantiopure 2,4-syn-Glu analogues 2b-p is accessed by a short and efficient chemoenzymatic approach starting from readily available cyclohexanone 3. Pharmacological characterization at the iGluRs and EAAT1-3 subtypes revealed analogue 2i as a selective GluK1 ligand with low nanomolar affinity. Two X-ray crystal structures of the key analogue 2i in the ligand-binding domain (LBD) of GluA2 and GluK3 were determined. Partial domain closure was seen in the GluA2-LBD complex with 2i comparable to that induced by kainate. In contrast, full domain closure was observed in the GluK3-LBD complex with 2i, similar to that of GluK3-LBD with glutamate bound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspartate Aminotransferases / chemistry
  • Brain / metabolism
  • Catalysis
  • Crystallography, X-Ray
  • Glutamate Plasma Membrane Transport Proteins / metabolism*
  • Glutamates / chemical synthesis*
  • Glutamates / chemistry
  • Glutamates / pharmacology
  • Glutamic Acid / analogs & derivatives*
  • Glutamic Acid / chemical synthesis
  • Glutamic Acid / chemistry
  • Glutamic Acid / pharmacology
  • HEK293 Cells
  • Humans
  • In Vitro Techniques
  • Ketoglutaric Acids / chemical synthesis
  • Ketoglutaric Acids / chemistry
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / chemistry
  • Receptors, AMPA / metabolism
  • Receptors, Ionotropic Glutamate / chemistry
  • Receptors, Ionotropic Glutamate / metabolism*
  • Receptors, Kainic Acid / chemistry
  • Receptors, Kainic Acid / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • (2S,4R)-4-(3-hydroxy(methyl)amino-3-oxopropyl)glutamic Acid
  • GluK3 kainate receptor
  • Gluk1 kainate receptor
  • Glutamate Plasma Membrane Transport Proteins
  • Glutamates
  • Ketoglutaric Acids
  • Ligands
  • Receptors, AMPA
  • Receptors, Ionotropic Glutamate
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Aspartate Aminotransferases
  • glutamate receptor ionotropic, AMPA 2

Associated data

  • PDB/4IGR
  • PDB/4IGT