title: 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 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.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ito
authors.forename: Akane
authors.initials: A
authors.lastname: Ishihara
authors.forename: Akira
authors.initials: A
authors.lastname: Gomori
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Egashira
authors.forename: Hiroko
authors.initials: H
authors.lastname: Matsushita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Mashiko
authors.forename: Junko
authors.initials: J
authors.lastname: Ito
authors.forename: Makoto
authors.initials: M
authors.lastname: Ito
authors.forename: Kazuho
authors.initials: K
authors.lastname: Nakase
authors.forename: Yuji
authors.initials: Y
authors.lastname: Haga
authors.forename: Hisashi
authors.initials: H
authors.lastname: Iwaasa
authors.forename: Takao
authors.initials: T
authors.lastname: Suzuki
authors.forename: Norikazu
authors.initials: N
authors.lastname: Ohtake
authors.forename: Minoru
authors.initials: M
authors.lastname: Moriya
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: MacNeil
authors.forename: Norihiro
authors.initials: N
authors.lastname: Takenaga
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tokita
authors.forename: Akio
authors.initials: A
authors.lastname: Kanatani
mesh_terms: 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
chemical_list: D019440:Anti-Obesity Agents; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor