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Discovery of Allosteric Potentiators for the Metabotropic Glutamate 2 Receptor:  Synthesis and Subtype Selectivity of N-(4-(2-Methoxyphenoxy)phenyl)-N-(2,2,2− trifluoroethylsulfonyl)pyrid-3-ylmethylamine

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Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285
Cite this: J. Med. Chem. 2003, 46, 15, 3189–3192
Publication Date (Web):June 12, 2003
https://doi.org/10.1021/jm034015u
Copyright © 2003 American Chemical Society

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    Abstract

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    This report describes recently discovered novel allosteric modulators of metabotropic glutamate2 (mGlu2) receptors. These pyridylmethylsulfonamides (e.g., 3) potentiate glutamate, shifting agonist potency by 2-fold. This effect was specific for mGlu2 (vs mGlu1,3−8 receptors). Also, 3 failed to potentiate a chimeric mGlu2/1 receptor, demonstrating the mGlu2 transmembrane region's critical involvement. In a fear-potentiated startle model, 3 showed anxiolytic activity that was prevented by mGlu2/3 antagonist pretreatment. Thus, these pyridylmethylsulfonamides represent the first mGlu2 receptor potentiators discovered.

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     To whom correspondence should be addressed. Phone:  317-277-6581. Fax:  317-276-5546. E-mail:  [email protected].

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    Synthetic methods and physicochemical properties of final products and intermediates shown in Scheme 1 and a more detailed description of the calcium assay methods and conditions utilized in binding selectivity assays. This material is available free of charge via the Internet at http://pubs.acs.org.

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