RESUMEN
Obesity remains a significant public health issue leading to Type II diabetes and cardiovascular disease. CB1 antagonists have been shown to suppress appetite and reduce body weight in animal models as well as in humans. Evaluation of pre-clinical CB1 antagonists to establish relationships between in vitro affinity and in vivo efficacy parameters are enhanced by ex vivo receptor occupancy data. Synthesis and biological evaluation of a novel and highly selective radiolabeled CB1 antagonist is described. The radioligand was used to conduct ex vivo receptor occupancy studies.
Asunto(s)
Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Ensayo de Unión Radioligante/métodos , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Humanos , Obesidad/tratamiento farmacológico , Radiografía , RatasRESUMEN
Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
Asunto(s)
Fármacos Antiobesidad/química , Obesidad/tratamiento farmacológico , Quinazolinonas/química , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/química , Administración Oral , Animales , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Humanos , Masculino , Obesidad/metabolismo , Unión Proteica/fisiología , Quinazolinonas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/metabolismoRESUMEN
In order to explore the relationship between the anorectic effect of 3-carboxy-4-octyl-2-methylenebutyrolactone (C75) and its pharmacokinetic properties, studies of in vivo and in vitro pharmacological characterization of C75 were performed in Fischer rats. In a quantitative measurement of food intake, we determined that appetite suppression by C75 takes place within 4 h. The C(max) for C75 of 2.6+/-1.5 microM was reached within 1-4 h after intraperitoneal administration at 30 mg/kg, a drug level that causes complete blockade of food intake. However, this concentration is substantially lower than the effective concentration used to inhibit rat fatty acid synthase enzyme activity in vitro (IC50: approximately 200 microM) and hypothalamic enzyme activity was found not to be inhibited by intraperitoneal administration of C75 at 30 mg/kg. Instead, a dramatic induction of c-Fos expression was found in area postrema. Collectively, these data indicate that the anorectic effect of C75 is independent of its inhibition of fatty acid synthase in the hypothalamus.