RESUMEN
A new class of indazole-derived bradykinin B(1) antagonists and their structure-activity relationships (SAR) is reported. A number of compounds were found to have low-nanomolar affinity for the human B(1) receptor and possess acceptable P-gp and pharmacokinetics properties.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Indazoles/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Humanos , Indazoles/farmacocinética , Unión Proteica , Relación Estructura-ActividadRESUMEN
The synthesis, structure-activity relationship (SAR), and pharmacological evaluation of analogs of the acid-sensing ion channel (ASIC) inhibitor A-317567 are reported. It was found that the compound with an acetylenic linkage was the most potent ASIC-3 channel blocker. This compound reversed mechanical hypersensitivity in the rat iodoacetate model of osteoarthritis pain, although sedation was noted. Sedation was also observed in ASIC-3 knockout mice, questioning whether sedation and antinociception are mediated via a non-ASIC-3 specific mechanism.
Asunto(s)
Bloqueadores del Canal Iónico Sensible al Ácido/síntesis química , Bloqueadores del Canal Iónico Sensible al Ácido/farmacología , Canales Iónicos Sensibles al Ácido/efectos de los fármacos , Analgésicos/síntesis química , Analgésicos/farmacología , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Naftalenos/síntesis química , Naftalenos/farmacología , Canales Iónicos Sensibles al Ácido/biosíntesis , Animales , Conducta Animal/efectos de los fármacos , Fenómenos Electrofisiológicos , Adyuvante de Freund , Yodoacetatos , Masculino , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Osteoartritis/inducido químicamente , Osteoartritis/tratamiento farmacológico , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Estimulación Física , Equilibrio Postural/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The CD1 family of proteins binds self and foreign glycolipids for presentation to CD1-restricted T cells. To identify previously uncharacterized active CD1 ligands, especially those of microbial origin, numerous glycolipids were synthesized and tested for their ability to stimulate mouse and human natural killer T (NKT) cells. They included analogs of the well known NKT cell agonist alpha-galactosyl ceramide (alpha-GalCer), bacterial glycolipids, and variations of the self-glycolipid, sulfatide. Bacterial glycolipids, alpha-galacturonosyl-ceramides from Sphingomonas wittichii, although structurally similar to alpha-GalCer, have significant differences in the sugar head group as well as the ceramide portion. The Sphingomonas glycosphingolipids (GSLs) and sulfatide variants were shown to activate human NKT cells as measured by IL-4 and IFN-gamma secretion. Moreover, CD1d-dimer staining revealed human NKT cell reactivity toward these GSLs and to the sulfatides in a fashion comparable with alpha-GalCer. Because alpha-GalCer is a marine-sponge-derived ligand, our study here shows that bacterium-derived antigens are also able to stimulate mouse and human NKT cells.
Asunto(s)
Antígenos Bacterianos/inmunología , Antígenos CD1/inmunología , Bacterias/inmunología , Glucolípidos/inmunología , Glicoesfingolípidos/inmunología , Células Asesinas Naturales/inmunología , Sphingomonas/inmunología , Animales , Antígenos Bacterianos/química , Antígenos CD1d , Línea Celular , Ceramidas/química , Glucolípidos/química , Humanos , Ratones , Modelos Moleculares , Conformación Molecular , Esfingosina/química , Linfocitos T/inmunologíaRESUMEN
Alpha-galactosyl ceramide has been identified to be a potent stimulatory agent for a novel immunological process, mediated by CD1 molecules. This paper describes a short and efficient synthesis of alpha-galactosyl ceramide. Starting from commercially available 2-deoxy galactose, a suitable sphingosine derivative was obtained in nine steps and 36% overall yield, which was subsequently glycosylated to give the target molecule. This flexible route will provide various glycolipids for further exploration of this interesting biological process.