Nociceptin/Orphanin FQ Peptide Receptor-Related Ligands as Novel Analgesics

Curr Top Med Chem. 2020;20(31):2878-2888. doi: 10.2174/1568026620666200508082615.


Despite similar distribution patterns and intracellular events observed in the nociceptin/ orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and nonpeptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptor- related ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.

Keywords: Anti-nociception; Bifunctional ligand; MOP receptor; NOP receptor; Non-human primate; Nonpeptide ligand; Peptide ligand; Spinal cord.

Publication types

  • Review

MeSH terms

  • Analgesics, Opioid / chemistry
  • Analgesics, Opioid / pharmacology*
  • Humans
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology*
  • Ligands
  • Naltrexone / analogs & derivatives*
  • Naltrexone / chemistry
  • Naltrexone / pharmacology
  • Pain / drug therapy
  • Phenylpropionates / chemistry
  • Phenylpropionates / pharmacology*
  • Receptors, Opioid / metabolism*


  • Analgesics, Opioid
  • BU10038
  • Isoquinolines
  • Ligands
  • Phenylpropionates
  • Receptors, Opioid
  • Naltrexone