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The mu-opioid receptor subtype is required for the anorectic effect of an opioid receptor antagonist.
Zhang, Jiaping; Frassetto, Andrea; Huang, Ruey-Ruey C; Lao, Julie Z; Pasternak, Alexander; Wang, Sheng-Ping; Metzger, Joseph M; Strack, Alison M; Fong, Tung M; Chen, Richard Z.
Afiliação
  • Zhang J; Department of Metabolic Disorders, Merck Research Laboratories, P.O. Box 2000, RY80M-213, Rahway, NJ 07065, USA.
Eur J Pharmacol ; 545(2-3): 147-52, 2006 Sep 18.
Article em En | MEDLINE | ID: mdl-16876155
A diaryl ether derivative, (6-(4-{[(3-methylbutyl)amino]methyl}phenoxy)nicotinamide, was prepared and investigated for its biochemical properties at cloned opioid receptors and its pharmacological effects on animal feeding. The compound displaced [(3)H]DAMGO binding of human mu-opioid receptor, [(3)H]U-69593 of human kappa-opioid receptor, and [(3)H]DPDPE of human delta-opioid receptor with IC(50) values of 0.5+/-0.2 nM, 1.4+/-0.2 nM, and 71+/-15 nM, respectively. The compound also potently inhibited [(3)H]DAMGO binding of cloned mouse and rat mu-opioid receptors (IC(50) approximately 1 nM), and acted as a competitive antagonist in a cAMP functional assay using cultured cells expressing human or mouse mu-opioid receptors. Following a single oral administration in diet-induced obese mice (at 10 or 50 mg/kg) or rats (at 1, 3, or 10 mg/kg), the compound caused a dose-dependent suppression of acute food intake and body weight gain in both species. Importantly, the anorectic efficacy of the compound was mostly diminished in mice deficient in the mu-opioid receptor. Our results suggest an important role for the mu-opioid receptor subtype in animal feeding regulation and support the development of mu-selective antagonists as potential agents for treating human obesity.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Depressores do Apetite / Receptores Opioides mu / Antagonistas de Entorpecentes Limite: Animals / Humans / Male Idioma: En Revista: Eur J Pharmacol Ano de publicação: 2006 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Holanda
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Depressores do Apetite / Receptores Opioides mu / Antagonistas de Entorpecentes Limite: Animals / Humans / Male Idioma: En Revista: Eur J Pharmacol Ano de publicação: 2006 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Holanda