Small-molecule melanin-concentrating hormone-1 receptor antagonists require brain penetration for inhibition of food intake and reduction in body weight.

The melanin-concentrating hormone-1 receptor (MCH1R) is a G-protein-coupled receptor expressed in the brain and peripheral tissues that regulates energy storage and body weight. Here, we focused on discovery of the mechanism and site of action for a small-molecule MCH1R antagonist, which yields weight loss in a mouse model of human obesity. MCH1R is expressed throughout the brain but also found in peripheral tissues known to regulate fat storage and utilization, e.g., skeletal muscle and adipose tissue. Previous studies of MCH1R antagonist studies have not delineated the site that is critical for mediating the anorexigenic and weight-reducing actions. In this study, we evaluated the role of the brain and peripheral tissue receptors. We developed a novel nonbrain-permeable MCH antagonist analog with a carboxylic acid moiety to specifically test the site of action. Based on in vitro and in vivo assays, the analog is not able to cross the blood-brain barrier and does not lead to inhibition of food intake and reduced body weight. The data clearly demonstrate that MCH1R antagonists need access to the brain to reduce body weight and fat mass. The brain-permeable MCH1R antagonist leads to significant reduction in body weight and fat mass in diet-induced obese mice. The effect is dose-dependent and appears to be partially driven by a reduction in food intake. Finally, these studies show the utility of a medicinal chemistry approach to address an important biological and pharmacological question.