The μ-opioid receptor subtype is required for the anorectic effect of an opioid receptor antagonist

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• 作者：Jiaping Zhang ; Andrea Frassetto ; Ruey-Ruey C. Huang ; Julie Z. Lao ; Alexander Pasternak ; Sheng-ping Wang ; Joseph M. Metzger ; Alison M. Strack ; Tung M. Fong and Richard Z. Chen
• 关键词：Opioid receptor antagonist ; Knockout mice ; Food intake ; Body weight
• 刊名：European Journal of Pharmacology
• 出版年：2006
• 出版时间：18 September 2006
• 年：2006
• 卷：545
• 期：2-3
• 页码：147-152
• 全文大小：241 K

文摘

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 [³H]DAMGO binding of human μ-opioid receptor, [³H]U-69593 of human κ-opioid receptor, and [³H]DPDPE of human δ-opioid receptor with IC₅₀ values of 0.5 ± 0.2 nM, 1.4 ± 0.2 nM, and 71 ± 15 nM, respectively. The compound also potently inhibited [³H]DAMGO binding of cloned mouse and rat μ-opioid receptors (IC₅₀ ≈ 1 nM), and acted as a competitive antagonist in a cAMP functional assay using cultured cells expressing human or mouse μ-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 μ-opioid receptor. Our results suggest an important role for the μ-opioid receptor subtype in animal feeding regulation and support the development of μ-selective antagonists as potential agents for treating human obesity.