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 discovery, synthesis and SAR of a novel series of 3-benzyl-1,3-oxazolidin-2-ones as positive allosteric modulators (PAMs) of mGluR2 is described. Expedient hit-to-lead work on a single HTS hit led to the identification of a ligand-efficient and structurally attractive series of mGluR2 PAMs. Human microsomal clearance and suboptimal physicochemical properties of the initial lead were improved to give potent, metabolically stable and orally available mGluR2 PAMs.
Assuntos
Carbamatos/química , Oxazolidinonas/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/química , Esquizofrenia/tratamento farmacológico , Administração Oral , Regulação Alostérica , Sítio Alostérico , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Microssomos/metabolismo , Modelos Químicos , Estrutura Molecular , Oxazolidinonas/químicaRESUMO
We hypothesize that nitroglycerin (NTG) causes direct oxidation of multiple cellular sulfhydryl (SH) proteins and that manipulation of SH redox status affects NTG tolerance. In LLC-PK1 cells, we found that nitrate tolerance, as indicated by cGMP accumulation toward NTG, was accompanied by increased protein [(35)S]cysteine incorporation, significant S-glutathionylation of multiple proteins, and decreased metabolic activity of several SH-sensitive enzymes, including creatine kinase, xanthine oxidoreductase, and glutaredoxin (GRX). Cells overexpressing GRX exhibited reduced cellular protein S-glutathionylation (PSSG) and absence of NTG tolerance, whereas those with silenced GRX showed increased extent of NTG-induced tolerance. Incubation of LLC-PK1 cells with oxidized glutathione led to several major observations associated with nitrate tolerance, namely, reduced cGMP accumulation, PSSG formation, superoxide accumulation, and the attenuation of these events by vitamin C. Aortic S-glutathionylated proteins increased approximately 3-fold in rats made tolerant in vivo to NTG and showed significant negative correlation with vascular responsiveness ex vivo. NTG incubation in EA.hy926 endothelial cells and LLC-PK1 cells led to increased S-glutathionylation and activity of p21(ras), a known mediator of cellular signaling. These results indicate that the hallmark events of NTG tolerance, such as reduced bioactivation and redox signaling, are associated with GRX-dependent protein deglutathionylation.
