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

• Published in: European journal of pharmacology 2009-12, Vol.624 (1), p.77-83
• Main Authors: Ito, Masahiko, Ishihara, Akane, Gomori, Akira, Egashira, Shinichiro, Matsushita, Hiroko, Mashiko, Satoshi, Ito, Junko, Ito, Makoto, Nakase, Kazuho, Haga, Yuji, Iwaasa, Hisashi, Suzuki, Takao, Ohtake, Norikazu, Moriya, Minoru, Sato, Nagaaki, MacNeil, Douglas J., Takenaga, Norihiro, Tokita, Shigeru, Kanatani, Akio
• Format: Article
• Language: English
• Subjects: Animal Feed; Animals; Anti-Obesity Agents - pharmacology; Anti-Obesity Agents - therapeutic use; Biological and medical sciences; Diet; Dose-Response Relationship, Drug; Medical sciences; Melanin-concentrating hormone 1-receptor Antagonist; Metabolic diseases; Mice; Obesity; Obesity - chemically induced; Obesity - drug therapy; Obesity - metabolism; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptor occupancy; Receptors, Pituitary Hormone - antagonists & inhibitors; Receptors, Pituitary Hormone - metabolism; Weight Gain - drug effects; Weight Gain - physiology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2009.10.004

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, [ 35S]-compound D. An MCH 1 receptor antagonist inhibited the binding of [ 35S]-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.