Melanin-concentrating hormone 1-receptor antagonist suppresses body weight gain correlated with high receptor occupancy levels in diet-induced obesity mice.
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 24h. Furthermore, more than 90% occupancy levels of MCH(1) receptor antagonists during 24h 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.
Ito
Masahiko
M
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
Ishihara
Akane
A
Gomori
Akira
A
Egashira
Shinichiro
S
Matsushita
Hiroko
H
Mashiko
Satoshi
S
Ito
Junko
J
Ito
Makoto
M
Nakase
Kazuho
K
Haga
Yuji
Y
Iwaasa
Hisashi
H
Suzuki
Takao
T
Ohtake
Norikazu
N
Moriya
Minoru
M
Sato
Nagaaki
N
MacNeil
Douglas J
DJ
Takenaga
Norihiro
N
Tokita
Shigeru
S
Kanatani
Akio
A
D000821:Animal Feed; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004032:Diet; D004305:Dose-Response Relationship, Drug; D051379:Mice; D009765:Obesity / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects* / Q000502:physiology
D019440:Anti-Obesity Agents; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor