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Mol Pharmacol. 2015 Sep;88(3):502-11. doi: 10.1124/mol.115.099150. Epub 2015 Jul 1.

Quantitative Signaling and Structure-Activity Analyses Demonstrate Functional Selectivity at the Nociceptin/Orphanin FQ Opioid Receptor.

Author information

1
Department of Psychiatry (S.D.C.), Department of Anesthesiology, Basic Research Division (S.D.C., S.M.S., M.R.B.), Department of Anatomy and Neurobiology (M.R.B.), Washington University Pain Center (M.R.B.), Division of Biology and Biomedical Sciences Program in Neuroscience (S.M.S., M.R.B.), Washington University School of Medicine, St. Louis, Missouri; RTI International (S.W.M., H.A.N., F.I.C.), Research Triangle Park, North Carolina; and Vanderbilt University, Nashville, Tennessee (V.V.G.).
2
Department of Psychiatry (S.D.C.), Department of Anesthesiology, Basic Research Division (S.D.C., S.M.S., M.R.B.), Department of Anatomy and Neurobiology (M.R.B.), Washington University Pain Center (M.R.B.), Division of Biology and Biomedical Sciences Program in Neuroscience (S.M.S., M.R.B.), Washington University School of Medicine, St. Louis, Missouri; RTI International (S.W.M., H.A.N., F.I.C.), Research Triangle Park, North Carolina; and Vanderbilt University, Nashville, Tennessee (V.V.G.) bruchasm@wustl.edu.

Abstract

Comprehensive studies that consolidate selective ligands, quantitative comparisons of G protein versus arrestin-2/3 coupling, together with structure-activity relationship models for G protein-coupled receptor (GPCR) systems are less commonly employed. Here we examine biased signaling at the nociceptin/orphanin FQ opioid receptor (NOPR), the most recently identified member of the opioid receptor family. Using real-time, live-cell assays, we identified the signaling profiles of several NOPR-selective ligands in upstream GPCR signaling (G protein and arrestin pathways) to determine their relative transduction coefficients and signaling bias. Complementing this analysis, we designed novel ligands on the basis of NOPR antagonist J-113,397 [(±)-1-[(3R*,4R*)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] to explore structure-activity relationships. Our study shows that NOPR is capable of biased signaling, and further, the NOPR selective ligands MCOPPB [1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-(3R)-3-piperidinyl-1H-benzimidazole trihydrochloride] and NNC 63-0532 [8-(1-naphthalenylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-3-acetic acid, methyl ester] are G protein-biased agonists. Additionally, minor structural modification of J-113,397 can dramatically shift signaling from antagonist to partial agonist activity. We explore these findings with in silico modeling of binding poses. This work is the first to demonstrate functional selectivity and identification of biased ligands at the nociceptin opioid receptor.

PMID:
26134494
PMCID:
PMC4551045
DOI:
10.1124/mol.115.099150
[Indexed for MEDLINE]
Free PMC Article

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