Melanin-concentrating hormone 1-receptor antagonist suppresses body weight gain correlated with high receptor occupancy levels in diet-induced obesity mice

Abstract Melanin-concentrating hormone (MCH), which is a neuropeptide expressed in the hypothalamus of the brain, is involved in regulating feeding behavior and energy homeostasis via the MCH 1 receptor in rodents. It is widely considered that MCH 1 receptor antagonists are worthy of development for medical treatment of obesity. Here we report on the development of an ex vivo receptor occupancy assay using a new radiolabeled MCH 1 receptor antagonist, [ 35 S]-compound D. An MCH 1 receptor antagonist inhibited the binding of [ 35 S]-compound D to brain slices in a dose-dependent manner. The result showed a good correlation between the receptor occupancy levels and plasma or brain levels of the MCH 1 receptor antagonist, suggesting that the ex vivo receptor binding assay using this radioligand is practical. Quantitative analysis in diet-induced obese mice showed that the efficacy of body weight reduction correlated with the receptor occupancy levels at 24 h. Furthermore, more than 90% occupancy levels of MCH 1 receptor antagonists during 24 h post-dosing are required for potent efficacy on body weight reduction. The present occupancy assay could be a useful pharmacodynamic marker to quantitatively estimate anti-obese efficacy, and would accelerate the development of MCH 1 receptor antagonists for treatment of obesity.