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

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  1 , 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
Affiliations

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 et al. J Med Chem. .

Erratum in

  • J Med Chem. 2013 Jul 25;56(14):5985

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.

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