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

Author(s): Norikazu Kiguchi*, Huiping Ding, Shiroh Kishioka, Mei-Chuan Ko

Journal Name: Current Topics in Medicinal Chemistry

Volume 20 , Issue 31 , 2020

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Graphical Abstract:


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, Non-human primate, NOP receptor, MOP receptor, Peptide ligand, Nonpeptide ligand, Spinal cord.

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Article Details

Year: 2020
Published on: 03 December, 2020
Page: [2878 - 2888]
Pages: 11
DOI: 10.2174/1568026620666200508082615
Price: $65

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