RESUMO
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.
Assuntos
Antipsicóticos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Imidazóis/síntese química , Piperidinas/síntese química , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica , Animais , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Disponibilidade Biológica , Encéfalo/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , Cães , Humanos , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Imidazóis/farmacocinética , Imidazóis/farmacologia , Técnicas In Vitro , Metanfetamina , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacologia , Conformação Proteica , Ensaio Radioligante , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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).