title: 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(4'-pyridylcarboxamido)morphinan (NAP) Modulating the Mu Opioid Receptor in a Biased Fashion.
abstract: Mounting evidence has suggested that G protein-coupled receptors can be stabilized in multiple conformations in response to distinct ligands, which exert discrete functions through selective activation of various downstream signaling events. In accordance with this concept, we report biased signaling of one C6-heterocyclic substituted naltrexamine derivative, namely, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(4'-pyridylcarboxamido)morphinan (NAP) at the mu opioid receptor (MOR). NAP acted as a low efficacy MOR partial agonist in the G protein-mediated [(35)S]GTPγS binding assay, whereas it did not significantly induce calcium flux or β-arrestin2 recruitment. In contrast, it potently blocked MOR full agonist-induced β-arrestin2 recruitment and translocation. Additionally, NAP dose-dependently antagonized MOR full agonist-induced intracellular calcium flux and β-arrestin2 recruitment. Further results in an isolated organ bath preparation confirmed that NAP reversed the morphine-induced reduction in colon motility. Ligand docking and dynamics simulation studies of NAP at the MOR provided more supporting evidence for biased signaling of NAP at an atomic level. Due to the fact that NAP is MOR selective and preferentially distributed peripherally upon systemic administration while β-arrestin2 is reportedly required for impairment of intestinal motility by morphine, biased antagonism of β-arrestin2 recruitment by NAP further supports its utility as a treatment for opioid-induced constipation.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University , 800 East Leigh Street, Richmond, Virginia 23298, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University , 800 East Leigh Street, Richmond, Virginia 23298, United States.|Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
authors.forename: Dwight A
authors.initials: DA
authors.lastname: Williams
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University , 800 East Leigh Street, Richmond, Virginia 23298, United States.
authors.forename: Saheem A
authors.initials: SA
authors.lastname: Zaidi
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University , 800 East Leigh Street, Richmond, Virginia 23298, United States.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England , 11 Hills Beach Road, Biddeford, Maine 04005, United States.
authors.forename: Amanda
authors.initials: A
authors.lastname: Braithwaite
authors.affiliation: Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England , 11 Hills Beach Road, Biddeford, Maine 04005, United States.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bilsky
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
authors.forename: Hamid I
authors.initials: HI
authors.lastname: Akbarali
authors.affiliation: Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England , 11 Hills Beach Road, Biddeford, Maine 04005, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Streicher
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D008958:Models, Molecular; D009019:Morphinans / Q000737:chemistry / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D009019:Morphinans; D017450:Receptors, Opioid, mu
keywords: Mu opioid receptor; NAP; biased signaling; functional selectivity; nalbuphine; β-arrestin2