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

Abstract 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 μ-opioid receptor, [ 3 H]U-69593 of human κ-opioid receptor, and [ 3 H]DPDPE of human δ-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 μ-opioid receptors (IC 50  ≈ 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.