Characterization of the nociceptin/orphanin FQ peptide receptor (NOP) as a novel pharmacological target for the development of safer analgesics

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The search for “safer” opioids is of highest clinical priority, underscored by the current opioid epidemic in certain countries. The nociceptin/orphanin FQ peptide receptor (NOP) is the fourth and still the least characterized member of the opioid receptor family. In principle, analgesia can be mediated by all four opioid receptors. Given the diminishing focus on biased agonism, multi-receptor targeting has been proposed as a novel concept to ameliorate unfavorable side effects by addressing multiple opioid receptors simultaneously with a single chemical entity. In fact, novel analgesics with bifunctional activity targeting the µ-opioid receptor (MOP) and NOP have been discovered, which proved to be more potent than morphine in chronic pain assays, but exhibiting fewer side effects. We have recently examined agonist-induced receptor phosphorylation and G protein signaling profiles of a series of chemically diverse mixed NOP-MOP agonists, which exhibited variable efficacies at NOP and MOP. This led us to the hypothesis that bifunctional NOP-MOP compounds with limited intrinsic activity might be promising lead structures for the development of novel opioids with increased therapeutic windows and reduced adverse effects. The present proposal will evaluate to what extent a combination of two parameters partial agonism in G protein signaling and low or absent agonist-induced receptor phosphorylation will provide predictive information for favorable analgesic therapeutic effects avoiding abuse liability. We will utilize a set of prototypical tool compounds with different balance of their NOP- and MOP-related effects including cebranopadol, AT-034, AT-324, AT-201 and AT-121. We have previously developed a panel of phosphosite-specific antibodies for NOP and MOP which enables us to assess different patterns of receptor activation in vivo and in vitro. We have also generated novel mouse models expressing phosphorylation-deficient as well as epitope-tagged NOP and MOP receptors. Using these novel tools, we will (1) evaluate acute respiratory depressant and reinforcing properties of prototypical bifunctional analgesics with different NOP-MOP balance; (2) analyse analgesic effects of bifunctional agonists in acute and chronic pain models using MOP and NOP knockout mice for target validation; (3) examine NOP and MOP phosphorylation under conditions of neuropathic pain using knockin mice expressing epitope-tagged receptors in combination with phosphosite-specific antibodies and (4) assess the role of NOP and MOP phosphorylation for receptor responsiveness in chronic pain models using total phosphorylation-deficient NOP and MOP mice.