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

Yan Zhang, Dwight A. Williams, Saheem A. Zaidi, Yunyun Yuan, Amanda Braithwaite, Edward J. Bilsky, William L. Dewey, Hamid I. Akbarali, John M. Streicher, Dana E. Selley

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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 [35S]GTP'S 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.

Original languageEnglish (US)
Pages (from-to)297-304
Number of pages8
JournalACS Chemical Neuroscience
Issue number3
StatePublished - Mar 16 2016
Externally publishedYes


  • biased signaling
  • functional selectivity
  • Mu opioid receptor
  • nalbuphine
  • NAP
  • β-arrestin2

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


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