17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(4'-pyridylcarboxamido)morphinan (NAP) Modulating the Mu Opioid Receptor in a Biased Fashion.

Title17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(4'-pyridylcarboxamido)morphinan (NAP) Modulating the Mu Opioid Receptor in a Biased Fashion.
Publication TypeJournal Article
Year of Publication2016
AuthorsZhang Y, Williams DA, Zaidi SA, Yuan Y, Braithwaite A, Bilsky EJ, Dewey WL, Akbarali HI, Streicher JM, Selley DE
JournalACS Chem Neurosci
Date Published2016 Mar 16
KeywordsAnalgesics, Opioid, Animals, Cell Line, CHO Cells, Cricetulus, Gastrointestinal Motility, Humans, Male, Mice, Microscopy, Confocal, Models, Molecular, Morphinans, Receptors, Opioid, mu

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.

Alternate JournalACS Chem Neurosci
PubMed ID26716358
PubMed Central IDPMC5111356
Grant ListDA024022 / DA / NIDA NIH HHS / United States
R01 DA024022 / DA / NIDA NIH HHS / United States
P20 GM103643 / GM / NIGMS NIH HHS / United States
R01 DA024009 / DA / NIDA NIH HHS / United States
R01 DA036975 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
John M. Streicher, PhD