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J Med Chem. 2016 Feb 11;59(3):914-24. doi: 10.1021/acs.jmedchem.5b01333. Epub 2016 Jan 27.

New 4-Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III.

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Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
Institute of Functional Genomics, CNRS, UMR5203, University of Montpellier , 34094 Montpellier, France.
INSERM, U1191 , 34094 Montpellier, France.
Institut de Chimie de Clermont-Ferrand, Clermont Université, Université Blaise Pascal, BP 10448 , 63000 Clermont-Ferrand, France.
CNRS, UMR6296, ICCF, BP 80026 , 63177 Aubière, France.
H. Lundbeck A/S , Ottiliavej 9, 2500 Valby, Denmark.


The metabotropic glutamate (Glu) receptors (mGluRs) play key roles in modulating excitatory neurotransmission in the brain. In all, eight subtypes have been identified and divided into three groups, group I (mGlu1,5), group II (mGlu2,3), and group III (mGlu4,6-8). In this article, we present a L-2,4-syn-substituted Glu analogue, 1d, which displays selective agonist activity at mGlu2 over the remaining mGluR subtypes. A modeling study and redesign of the core scaffold led to the stereoselective synthesis of four new conformationally restricted Glu analogues, 2a-d. Most interestingly, 2a retained a selective agonist activity profile at mGlu2 (EC50 in the micromolar range), whereas 2c/2d were both selective agonists at group III, subtypes mGlu4,6,8. In general, 2d was 20-fold more potent than 2c and potently activated mGlu4,6,8 in the low-mid nanomolar range.

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