RESUMEN
Structure-activity relationships of a 4-aminoquinoline MCH1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4-, and 6-positions of the original HTS hit. Improvements to the original screening lead included lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl, and hydrocinnamyl carboxamides at the 6-position. Modifications of the 4-amino group were not well tolerated.
Asunto(s)
Aminoquinolinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Unión Competitiva , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Técnicas In Vitro , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Structure-activity relationship studies directed toward the optimization of 4,5-diarylimidazole-2-carboxamide analogs as human CB1 receptor inverse agonists resulted in the discovery of the two amide derivatives 24a and b (hCB1 IC50 = 6.1 and 4.0 nM) which also demonstrated efficacy in overnight feeding studies in the rat for reduction in both food intake and overall body weight.
Asunto(s)
Imidazoles/síntesis química , Imidazoles/farmacología , Obesidad/tratamiento farmacológico , Receptor Cannabinoide CB1/efectos de los fármacos , Animales , Área Bajo la Curva , Unión Competitiva/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Humanos , Imidazoles/farmacocinética , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Melanin-concentrating hormone (MCH) exerts a positive regulation on appetite and binds to the G protein-coupled receptors, MCH1R and MCH2R. In rodents, MCH is produced by neurons in the lateral hypothalamus with projections to various hypothalamic and other brain sites. In the present study, MCH1R was shown, by immunocytochemistry, to be present in the human infundibular nucleus/median eminence, paraventricular nucleus, lateral hypothalamic area, and perifornical area, although in the latter two regions, only a few MCH1R-containing cells were found. In addition, MCH1R staining was found in nerve fibers in the periventricular nucleus, dorsomedial and ventromedial nucleus, suprachiasmatic nucleus, and tuberomammillary nucleus. A significant 1.6 times increase in the number of MCH1R cell body staining was found in the infundibular nucleus in postmortem brain material of cachectic patients, compared with matched controls, supporting a role for this receptor in energy homeostasis in the human.
Asunto(s)
Núcleo Arqueado del Hipotálamo/química , Caquexia/metabolismo , Receptores de Somatostatina/análisis , Anciano , Anciano de 80 o más Años , Animales , Femenino , Humanos , Hipotálamo/química , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Conejos , RatasRESUMEN
The peptides alpha-melanocyte stimulating hormone (alpha-MSH) and oxytocin, when administered centrally, produce similar behavioral effects. alpha-MSH induces Fos expression in supraoptic oxytocin neurons, and alpha-MSH melanocortin-4 receptors (MC4Rs) are highly expressed in the supraoptic nucleus, suggesting that alpha-MSH and oxytocin actions are not independent. Here we investigated the effects of alpha-MSH on the activity of supraoptic neurons. We confirmed that alpha-MSH induces Fos expression in the supraoptic nucleus when injected centrally and demonstrated that alpha-MSH also stimulates Fos expression in the nucleus when applied locally by retrodialysis. Thus alpha-MSH-induced Fos expression is not associated with electrophysiological excitation of supraoptic neurons because central injection of alpha-MSH or selective MC4 receptor agonists inhibited the electrical activity of oxytocin neurons in the supraoptic nucleus recorded in vivo. Consistent with these observations, oxytocin secretion into the bloodstream decreased after central injection of alpha-MSH. However, MC4R ligands induced substantial release of oxytocin from dendrites in isolated supraoptic nuclei. Because dendritic oxytocin release can be triggered by changes in [Ca2+]i, we measured [Ca2+]i responses in isolated supraoptic neurons and found that MC4R ligands induce a transient [Ca2+]i increase in oxytocin neurons. This response was still observed in low extracellular Ca2+ concentration and probably reflects mobilization of [Ca2+]i from intracellular stores rather than entry via voltage-gated channels. Taken together, these results show for the first time that a peptide, here alpha-MSH, can induce differential regulation of dendritic release and systemic secretion of oxytocin, accompanied by dissociation of Fos expression and electrical activity.