Small-Molecule Melanin-Concentrating Hormone-1 Receptor Antagonists Require Brain Penetration for Inhibition of Food Intake and Reduction in Body Weight

Abstract

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 brainpermeable 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.The obesity epidemic continues to increase in many developed and developing countries (Ogden et al., 2003;Haslam and James, 2005). The 2004 National Health and Nutrition Examination Survey indicated that more than 50% of the United States population is either obese or overweight (Hedley et al., 2004;Ogden et al., 2006). More importantly, the incidence of obese and overweight children is also on the rise. Obesity is associated with multiple metabolic disorders, including diabetes and cardiovascular disease (Ogden et al., 2003). There is a great interest in identifying behavioral and pharmacological approaches to reduce body weight in obese and overweight individuals.Weight loss intervention strategies include targets for reducing hunger/appetite, enhancing satiety, increasing metabolism/ energy utilization, blocking fat absorption, inhibiting adipose tissue differentiation, and inducing adipose tissue apoptosis. The current therapeutic approaches for weight loss include diet, exercise, and pharmacotherapy. Efficacy is very modest, with a high rate of recidivism at the end of the treatment period (Schnee et al., 2006). Orlistat (Xenical) and sibutramine (Meridia) are currently the only two approved pharmacotherapy agents on the market. Orlistat blocks absorption of fat from the intestine, whereas sibutramine reduces appetite by acting on brain pathways that regulate hunger (Bray and Ryan, 2007). These drugs show limited efficacy, and considerable attention is focused on the development of new reagents to decrease body weight.

Recent Updates on the Melanin-Concentrating Hormone (MCH) and Its Receptor System: Lessons from MCH1R Antagonists

“…Numerous small-molecule MCH1R antagonists have since been developed and have consistently been effective in animal models of DIO (Borowsky et al 2002; Eric Hu et al 2008; Gehlert et al 2009; Ito et al 2010; Kowalski et al 2006; Luthin 2007; Mashiko et al 2005), reviewed in (Luthin 2007; McBriar 2006). Chronic administration of MCH1R antagonists successfully decreased food intake and body weight gain induced by high calorific food consumption.…”

“…The central MCH system seems to play an important role in regulating energy balance and metabolism since Mashiko et al (2005) showed that chronic central infusions of a peptide MCH1R antagonist into DIO mice only slightly decreased food intake but significantly reduced body weight. Another study reported that only MCH1R antagonists which can cross the blood brain barrier (BBB) are able to decrease food intake and body weight, while those that do not are ineffective (Eric Hu et al 2008). However, the BBB-crossing antagonist used in this study also induced a modest conditioned taste aversion (Eric Hu et al 2008), which complicates interpretation of these results.…”

“…Another study reported that only MCH1R antagonists which can cross the blood brain barrier (BBB) are able to decrease food intake and body weight, while those that do not are ineffective (Eric Hu et al 2008). However, the BBB-crossing antagonist used in this study also induced a modest conditioned taste aversion (Eric Hu et al 2008), which complicates interpretation of these results. Additional studies found that central MCH1R antagonist injection reduced MCH-induced food intake but failed to decrease spontaneous food intake when it was injected alone (Audinot et al 2009; Morens et al 2005).…”

Inflammation-induced functional connectivity of melanin-concentrating hormone and IL-10

“…IL-10 deficient mice were treated with the small molecule MCHR1 antagonist DABA-822. While administration of this compound does not modulate food intake or body weight in mice, presumably due to its lack of brain penetration, it has been shown to reduce the severity of TNBS-induced colitis [15]. We found that the beneficial effects of blocking MCH in experimental colitis were cancelled in the absence of IL-10, suggesting perhaps a cross-talk between MCH and IL-10.…”

“…DABA-822 is a small molecule MCHR1 antagonist with only peripheral effects due to its limited brain penetration [15]. Previous studies have demonstrated attenuation of TNBS-induced experimental colitis in mice treated with DABA-822 [7].…”