Abstract
A series of compounds based on the mGluR5-selective ligand 2-methyl-6-(phenylethynyl)pyridine (MPEP) were designed and synthesized. The compounds were found to be either structural analogues of MPEP, substituted monomers, or dimeric analogues. All compounds retained mGluR5 selectivity with only weak or no activity at other mGluRs or iGluRs. The substituted analogue, 1,3-bis(pyridin-2-ylethynyl)benzene (19), is a potent negative modulator at mGluR5, whereas all other compounds lost potency relative to MPEP and showed that activity is highly dependent on the position of the nitrogen atom in the pyridine moieties. A homology modeling and ligand docking study was used to understand the binding mode and the observed selectivity of compound 19.
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkynes / chemical synthesis*
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Alkynes / pharmacology
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Alkynes / therapeutic use
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Allosteric Regulation
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Amino Acid Sequence
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Animals
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Anti-Anxiety Agents / chemical synthesis*
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Anti-Anxiety Agents / pharmacology
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Anti-Anxiety Agents / therapeutic use
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Anxiety Disorders / drug therapy*
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Anxiety Disorders / metabolism
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Binding Sites
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Brain / drug effects
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Brain / metabolism
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CHO Cells
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Cricetinae
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Dimerization
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Glutamic Acid / metabolism
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Humans
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Models, Molecular
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Molecular Sequence Data
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Protein Binding
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Pyridines / chemical synthesis*
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Pyridines / pharmacology
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Pyridines / therapeutic use
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate / antagonists & inhibitors*
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Receptors, Metabotropic Glutamate / metabolism
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Structure-Activity Relationship
Substances
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1,3-bis(pyridin-2-ylethynyl)benzene
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Alkynes
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Anti-Anxiety Agents
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GRM5 protein, human
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Pyridines
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate
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Glutamic Acid