• Journal Article

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

Citation

Chang, S. D., Mascarella, S., Spangler, S., Gurevich, V. V., Navarro, H., Carroll, F., & Bruchas, M. R. (2015). Quantitative Signaling and Structure-Activity Analyses Demonstrate Functional Selectivity at the Nociceptin/Orphanin FQ Opioid Receptor. Molecular Pharmacology, 88(3), 502-511. DOI: 10.1124/mol.115.099150

Abstract

Comprehensive studies that consolidate selective ligands, quantitative comparisons of G-protein versus arrestin2/3 coupling, together with structure-activity relationship models (SAR) 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've identified the signaling profiles of several NOPR-selective ligands in upstream GPCR signaling (G-protein and arrestin pathways), in order to determine their relative transduction coefficients and signaling bias. Complementing this analysis, we designed novel ligands based on the NOPR antagonist J-113,397 to explore structure activity relationships. Our study shows that NOPR is capable of biased signaling, and further the NOPR selective ligands MCOPPB and NNC 63-0532 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