title: The mu-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 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.
authors.affiliation: Department of Metabolic Disorders, Merck Research Laboratories, P.O. Box 2000, RY80M-213, Rahway, NJ 07065, USA.
authors.forename: Jiaping
authors.initials: J
authors.lastname: Zhang
authors.forename: Andrea
authors.initials: A
authors.lastname: Frassetto
authors.forename: Ruey-Ruey C
authors.initials: RR
authors.lastname: Huang
authors.forename: Julie Z
authors.initials: JZ
authors.lastname: Lao
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Wang
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
authors.forename: Alison M
authors.initials: AM
authors.lastname: Strack
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: Richard Z
authors.initials: RZ
authors.lastname: Chen
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009292:Narcotic Antagonists / Q000494:pharmacology*; D051381:Rats; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000145:classification / Q000502:physiology*
chemical_list: D001067:Appetite Depressants; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-