RESUMEN
We herein report the discovery of a novel class of antagonists of the human adenosine A2B receptor. This low molecular weight scaffold has been optimized to offer derivatives with potential utility for the alleviation of conditions associated with this receptor subtype, such as nociception, diabetes, asthma and COPD. Furthermore, preliminary pharmacokinetic analysis has revealed compounds with profiles suitable for either inhaled or systemic routes of administration.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Pirimidinas/química , Administración por Inhalación , Animales , Asma/tratamiento farmacológico , Diseño de Fármacos , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Receptor de Adenosina A2A/metabolismo , Receptor de Adenosina A2B/metabolismoRESUMEN
The cannabinoid CB1 receptor inverse agonist rimonabant induces hypophagia and body weight loss. Reduced body weight may potentially be due to decreased food intake or to direct metabolic effects of drug administration on energy expenditure. This study uses a paired-feeding protocol to quantify the contributions of energy intake to rimonabant-induced body weight loss. Diet-induced obese (DIO) rats were dosed with rimonabant (3, 10 mg/kg PO once daily) and matched with pair-fed controls. Food intake and body weight were measured daily. Blood samples and adipose tissue were collected on day 15 for measurement of plasma adiponectin and adiponectin mRNA levels. DIO rats treated with rimonabant and pair-fed controls showed very similar changes in body weight. Although tolerance developed to the anorectic effect of rimonabant, total food intake was significantly decreased over the 14-day study period and fully accounted for the observed reductions in body weight. Adiponectin mRNA and plasma adiponectin were elevated in vehicle-treated chow-fed animals compared to obese controls, and did not differ between rimonabant-treated and pair-fed animals. The similarities between rimonabant-treated and pair-fed animals in body weight loss and the absence of differences in measures of adiponectin activity between drug-treated and pair-fed animals suggest that the outcomes of this experiment were solely mediated by the drug-induced reduction in food intake.
Asunto(s)
Adiponectina/fisiología , Peso Corporal/efectos de los fármacos , Grasas de la Dieta/administración & dosificación , Ingestión de Alimentos/efectos de los fármacos , Obesidad/fisiopatología , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Adiponectina/biosíntesis , Adiponectina/sangre , Animales , Masculino , Ratas , Ratas Sprague-Dawley , RimonabantRESUMEN
A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.