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.
Subject(s)
Antipsychotic Agents/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Imidazoles/chemical synthesis , Piperidines/chemical synthesis , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation , Animals , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Biological Availability , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line , Dogs , Humans , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , In Vitro Techniques , Methamphetamine , Mice , Microsomes, Liver/metabolism , Models, Molecular , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protein Conformation , Radioligand Assay , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationship (SAR) of a novel series of 3-(imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers, derived from a high throughput screening (HTS), are described. Subsequent optimization led to identification of potent, metabolically stable and orally available mGluR2 positive allosteric modulators (PAMs).
