%0 Journal Article
%T In vitro pharmacological characterization of a novel unbiased NOP receptor©\selective nonpeptide agonist AT©\403
%A Blair V. Journigan
%A Claudio Trapella
%A David G. Lambert
%A Davide Malfacini
%A Federica Ferrari
%A Girolamo Calo'
%A Mark F. Bird
%A Nurulain T. Zaveri
%A Remo Guerrini
%J Archive of "Pharmacology Research & Perspectives".
%D 2017
%R 10.1002/prp2.333
%X Nociceptin/orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP), a member of the opioid receptor family. We recently identified a new high affinity and highly selective NOP agonist AT©\403. In this study, we characterized the functional profile of AT©\403 and compared it to other known nonpeptide NOP agonists Ro 65©\6570, Ro 2q, SCH©\221510, MCOPPB, AT©\202 and SCH©\486757, using the following assays: GTP ¦Ã[35S] stimulated binding, calcium mobilization assay in cells©\expressing human NOP or classical opioid receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, and the electrically stimulated mouse vas deferens bioassay. All compounds behaved as NOP full agonists consistently showing the following rank order of potency MCOPPB > AT©\403 > Ro 65©\6570 = Ro 2q > SCH©\221510 > AT©\202 > SCH©\486757. AT©\403 and MCOPPB displayed the highest NOP selectivity both at human and murine receptors. Interestingly, while all the other nonpeptide NOP agonists displayed bias toward G protein©\mediated signaling in the BRET assay, AT©\403, similar to the natural ligand N/OFQ, behaved as an unbiased agonist, activating G©\protein©\mediated function as well as arrestin recruitment. AT©\403 may be a useful nonpeptide tool compound to study the pharmacology of NOP activation in disease states
%K BRET arrestin assay
%K functional selectivity
%K GPCR signaling bias
%K ligand bias
%K nonpeptide NOP agonists
%K NOP receptor
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684865/