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

Zeinab Assaf; Anja P Larsen; Raminta Venskutonytė; Liwei Han; Bjarke Abrahamsen; Birgitte Nielsen; Michael Gajhede; Jette S Kastrup; Anders A Jensen; Darryl S Pickering; Karla Frydenvang; Thierry Gefflaut; Lennart Bunch

doi:10.1021/jm301433m

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.

Authors

Zeinab Assaf¹, Anja P Larsen, Raminta Venskutonytė, Liwei Han, Bjarke Abrahamsen, Birgitte Nielsen, Michael Gajhede, Jette S Kastrup, Anders A Jensen, Darryl S Pickering, Karla Frydenvang, Thierry Gefflaut, Lennart Bunch

Affiliation

¹ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen Ø, Denmark.

PMID: 23414088
DOI: 10.1021/jm301433m

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
GluK3 Kainate Receptor
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
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