RTI uses cookies to offer you the best experience online. By clicking “accept” on this website, you opt in and you agree to the use of cookies. If you would like to know more about how RTI uses cookies and how to manage them please view our Privacy Policy here. You can “opt out” or change your mind by visiting: http://optout.aboutads.info/. Click “accept” to agree.
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
