1 research outputs found
17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(4′-pyridylcarboxamido)morphinan (NAP) Modulating the Mu Opioid Receptor in a Biased Fashion
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)Âmorphinan
(NAP) at the mu opioid receptor (MOR). NAP acted as a low efficacy
MOR partial agonist in the G protein-mediated [<sup>35</sup>S]ÂGTPγS
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