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Papers of the Week

Papers: 8 May 2021 - 14 May 2021

Human Studies, Pharmacology/Drug Development

2021 May 06

Mol Pharmacol

Differential In vitro Pharmacological Profiles of Structurally Diverse Nociceptin Receptor Agonists in Activating G-protein and Beta-arrestin Signaling at the Human Nociceptin Opioid Receptor.


Agonists at the nociceptin opioid peptide receptor (NOP) are under investigation as therapeutics for non-addicting analgesia, opioid use disorder, Parkinson's disease, and other indications. NOP full and partial agonists have both been of interest, particularly since NOP partial agonists show a reduced propensity for behavioral disruption than NOP full agonists. Here, we investigated the in vitro pharmacological properties of chemically diverse NOP receptor agonists in assays measuring functional activation of the NOP receptor such as GTPgS binding, cAMP inhibition, GIRK activation, phosphorylation, β-arrestin recruitment and receptor internalization. When normalized to the efficacy of the natural agonist nociceptin/orphanin FQ (N/OFQ), we found that different functional assays that measure intrinsic activity produce inconsistent levels of agonist efficacy, particularly for ligands that were partial agonists. Agonist efficacy obtained in the GTPgS assay tended to be lower than that in the cAMP and GIRK assays. These structurally diverse NOP agonists also showed differential receptor phosphorylation profiles at the phosphosites we examined and induced varying levels of receptor internalization. Interestingly, while the rank order for β-arrestin recruitment by these NOP agonists was consistent with their ability to induce receptor internalization, their phosphorylation signatures at the timepoint we investigated were not indicative of the levels of β-arrestin recruitment or internalization induced by these agonists. It is possible that other phosphorylation sites, yet to be identified, drive the recruitment of NOP receptor ensembles and subsequent receptor trafficking by some nonpeptide NOP agonists. These findings potentially help understand NOP agonist pharmacology in the context of ligand-activated receptor trafficking. Chemically diverse agonist ligands at the nociceptin opioid receptor GPCR showed differential efficacy for activating downstream events after receptor binding, in a suite of functional assays measuring GTPγS binding, cAMP inhibition, GIRK channel activation, β-arrestin recruitment, receptor internalization and receptor phosphorylation. These analyses provide a context for understanding NOP agonist pharmacology driven by ligand-induced differential NOP receptor signaling.