RESUMEN
The synthesis, SAR and binding affinities are described for cannabinoid-1 receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
Asunto(s)
Agonistas de Receptores de Cannabinoides , Obesidad/tratamiento farmacológico , Pirimidinas/química , Administración Oral , Animales , Cannabinoides/química , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Estructura Terciaria de Proteína , Ratas , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Relación Estructura-ActividadRESUMEN
Structure-activity relationship studies for two series of 2-benzyloxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyridines having either a 3-cyano or 3-carboxamide moiety resulted in the preparation of the 2-(3,4-difluorobenzyloxy)-3-nitrile analog 10d and the 2-(3,4-difluorobenzyloxy)-3-(N-propylcarboxamide) analog 16c, (hCB1 IC(50)=1.3 and 1.7 nM, respectively) as potent and selective hCB1 inverse agonists. Their synthesis and biological activities are described herein.
Asunto(s)
Piridinas/síntesis química , Receptor Cannabinoide CB1/agonistas , Animales , Disponibilidad Biológica , Células CHO , Cricetinae , Humanos , Concentración 50 Inhibidora , Masculino , Piridinas/farmacocinética , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Distribución Tisular , TransfecciónRESUMEN
Central administration of the neuropeptide melanin-concentrating hormone (MCH) stimulates feeding in rodents. We studied the effects of intracerebroventricular (i.c.v.) administration of an MCH-1 receptor agonist (Compound A) and an MCH-1 receptor antagonist (Compound B) on feeding in satiated rats. Compound B (10 microg, i.c.v.) blocked the acute orexigenic effect of Compound A (5 microg, i.c.v.). In an experiment designed to either stimulate or inhibit MCH-1 receptor signaling over an extended period, rats received continuous i.c.v. infusions of vehicle (saline), Compound A (30 microg/day), Compound B (30 or 48 microg/day) or neuropeptide Y (24 microg/day, as positive control) via implantable infusion pumps. Continuous MCH-1 receptor activation recapitulated the obese phenotype of MCH-over-expressor mice, manifest as enhanced feeding (+23%, P<0.001), caloric efficiency and body weight gain (+38%, P<0.005) over the 14-day period relative to controls. Chronic MCH-1 receptor activation also elevated plasma insulin and leptin levels significantly. Conversely, continuous MCH-1 receptor antagonism led to sustained reductions in food intake (-16%, P<0.001), body weight gain (-35%, P<0.01), and body fat gain relative to controls, without an effect on lean mass. Antagonism of the MCH-1 receptor may be an effective approach for the treatment of obesity.