RESUMEN
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.
Asunto(s)
Antipsicóticos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Imidazoles/síntesis química , Piperidinas/síntesis química , Receptores de Glutamato Metabotrópico/metabolismo , Regulación Alostérica , Animales , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Disponibilidad Biológica , Encéfalo/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular , Perros , Humanos , Hipercinesia/inducido químicamente , Hipercinesia/tratamiento farmacológico , Imidazoles/farmacocinética , Imidazoles/farmacología , Técnicas In Vitro , Metanfetamina , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacología , Conformación Proteica , Ensayo de Unión Radioligante , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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).
