title: Pharmacological Profile of Nociceptin/Orphanin FQ Receptors Interacting with G-Proteins and β-Arrestins 2.
abstract: Nociceptin/orphanin FQ (N/OFQ) controls several biological functions by selectively activating an opioid like receptor named N/OFQ peptide receptor (NOP). Biased agonism is emerging as an important and therapeutically relevant pharmacological concept in the field of G protein coupled receptors including opioids. To evaluate the relevance of this phenomenon in the NOP receptor, we used a bioluminescence resonance energy transfer technology to measure the interactions of the NOP receptor with either G proteins or β-arrestin 2 in the absence and in presence of increasing concentration of ligands. A large panel of receptor ligands was investigated by comparing their ability to promote or block NOP/G protein and NOP/arrestin interactions. In this study we report a systematic analysis of the functional selectivity of NOP receptor ligands. NOP/G protein interactions (investigated in cell membranes) allowed a precise estimation of both ligand potency and efficacy yielding data highly consistent with the known pharmacological profile of this receptor. The same panel of ligands displayed marked differences in the ability to promote NOP/β-arrestin 2 interactions (evaluated in whole cells). In particular, full agonists displayed a general lower potency and for some ligands an inverted rank order of potency was noted. Most partial agonists behaved as pure competitive antagonists of receptor/arrestin interaction. Antagonists displayed similar values of potency for NOP/Gβ1 or NOP/β-arrestin 2 interaction. Using N/OFQ as reference ligand we computed the bias factors of NOP ligands and a number of agonists with greater efficacy at G protein coupling were identified.
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Malfacini
authors.affiliation: Department of Pharmacology, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ambrosio
authors.affiliation: Department of Pharmacology, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Gro'
authors.affiliation: Department of Pharmacology, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sbraccia
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, Ferrara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Trapella
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, Ferrara, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Department of Morphology, Surgery, and Experimental Medicine, Section of Pathology, Oncology, and Experimental Biology and LTTA, University of Ferrara, Ferrara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bonora
authors.affiliation: Department of Morphology, Surgery, and Experimental Medicine, Section of Pathology, Oncology, and Experimental Biology and LTTA, University of Ferrara, Ferrara, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Pinton
authors.affiliation: Department of Pharmacology, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Costa
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Calo'
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D019390:Arrestins / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009292:Narcotic Antagonists / Q000494:pharmacology*; D011485:Protein Binding; D011957:Receptors, Opioid / Q000378:metabolism*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000094942:Nociceptin Receptor
chemical_list: C000605254:ARRB2 protein, human; D000701:Analgesics, Opioid; D019390:Arrestins; D008024:Ligands; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D019204:GTP-Binding Proteins; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human