RESUMEN
In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, we prepared a novel series of phenoxypropanolamine derivatives containing the thiourea moiety and evaluated their biological activities at human beta3-, beta2-, and beta1-ARs. Among these compounds, 4-nitrophenylthiourea (18i) and 3-methoxyphenylthiourea (18k) derivatives were found to exhibit potent agonistic activity at the beta3-AR, with EC(50) values of 0.10 and 0.16 microM, respectively, and no agonistic activity for either the beta1- or beta2-AR. In addition, they showed significant hypoglycemic activity in a rodent diabetic model.
Asunto(s)
Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Fenoxipropanolaminas/química , Fenoxipropanolaminas/uso terapéutico , Receptores Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos/síntesis química , Agonistas Adrenérgicos/farmacología , Antagonistas de Receptores Adrenérgicos beta 3 , Animales , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Ratones , Estructura Molecular , Obesidad/tratamiento farmacológico , Fenoxipropanolaminas/síntesis química , Fenoxipropanolaminas/farmacología , Receptores Adrenérgicos beta 3/metabolismo , Relación Estructura-Actividad , Tiourea/síntesis química , Tiourea/química , Tiourea/farmacología , Tiourea/uso terapéuticoRESUMEN
Microscopic colitis is the most common cause of chronic watery diarrhea, with normal mucosal appearance during colonoscopy. The diagnosis is made by pathological examination of biopsy specimens showing colitis with normal architecture of the mucosa. The two most frequent forms of microscopic colitis are lymphocytic colitis and collagenous colitis, but other atypical variants have been described. We report a case of lymphocytic colitis with multinucleated large cells and we discuss a variant of giant cells microscopic colitis.
Asunto(s)
Colitis Linfocítica/patología , Células Gigantes/patología , Mucosa Intestinal/patología , Anciano , Biopsia , Colitis Linfocítica/tratamiento farmacológico , Colonoscopía , Humanos , Hidrocortisona/uso terapéutico , Loperamida/uso terapéutico , Losartán/uso terapéutico , Masculino , Fenoxipropanolaminas/uso terapéutico , Tiroxina/uso terapéuticoRESUMEN
We have previously shown that antinociceptive effects of morphine are enhanced in histamine H1 receptor gene knockout mice. In the present study, involvement of supraspinal histamine H2 receptor in antinociception by morphine was examined using histamine H2 receptor gene knockout (H2KO) mice and histamine H2 receptor antagonists. Antinociception was evaluated by assays for thermal (hot-plate, tail-flick and paw-withdrawal tests), mechanical (tail-pressure test) and chemical (formalin and capsaicin tests) stimuli. Thresholds for pain perception in H2KO mice were higher than wild-type mice. Antinociceptive effects of intracerebroventricularly administered morphine were enhanced in the H2KO mice compared to wild-type mice. Intracerebroventricular co-administration of morphine and cimetidine produced significant antinociceptive effects in the wild-type mice when compared to morphine or cimetidine alone. Furthermore, zolantidine, a selective and hydrophobic H2 receptor antagonist, enhanced the effects of morphine in all nociceptive assays examined. These results suggest that histamine exerts inhibitory effects on morphine-induced antinociception through H2 receptors at the supraspinal level. Our present and previous studies suggest that H1 and H2 receptors cooperatively function to modulate pain perception in the central nervous system.