Abstract
A novel series of mGluR2 positive allosteric modulators (PAMs), 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, is herein disclosed. Structure-activity relationship studies led to potent, selective mGluR2 PAMs with excellent pharmacokinetic profiles. A representative lead compound (+)-17e demonstrated dose-dependent inhibition of methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, providing support for potential efficacy in treating psychosis.
MeSH terms
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Allosteric Regulation
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Animals
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Antipsychotic Agents / chemical synthesis*
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Antipsychotic Agents / pharmacokinetics
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Antipsychotic Agents / pharmacology
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Biological Availability
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Brain / metabolism
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Line
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Dogs
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Humans
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Hyperkinesis / chemically induced
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Hyperkinesis / drug therapy
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacokinetics
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Imidazoles / pharmacology
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In Vitro Techniques
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Methamphetamine
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Mice
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Microsomes, Liver / metabolism
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Models, Molecular
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Protein Conformation
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Radioligand Assay
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Rats
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Receptors, Metabotropic Glutamate / metabolism*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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1-methyl-2-((3-methyl-4-(4-trifluoromethyl-2-fluoro)phenyl)piperidin-1-ylmethyl)-1H-imidazo(4,5-b)pyridine
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Antipsychotic Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Imidazoles
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Piperidines
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Receptors, Metabotropic Glutamate
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metabotropic glutamate receptor 2
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Methamphetamine