As clinical use of currently available opioid analgesics is often impeded by dose-limiting adverse effects, such as abuse liability and respiratory depression, new approaches have been pursued to develop safe, effective, and non-addictive pain medications. After the identification of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor more than 25 years ago, NOP receptor-related agonists have emerged as a promising target for developing novel and effective opioids that modulate the analgesic and addictive properties of mu-opioid peptide (MOP) receptor agonists. In this review, we highlight the effects of the NOP receptor-related agonists compared with those of MOP receptor agonists in experimental rodent and more translational non-human primate (NHP) models and the development status of key NOP receptor-related agonists as potential safe and non-addictive analgesics. Several lines of evidence demonstrated that peptidic and non-peptidic NOP receptor agonists produce potent analgesic effects by intrathecal delivery in NHPs. Moreover, mixed NOP/MOP receptor partial agonists (e.g., BU08028, BU10038, and AT-121) display potent analgesic effects when administered intrathecally or systemically, without eliciting adverse effects, such as respiratory depression, itch behavior, and signs of abuse liability. More importantly, cebranopadol, a mixed NOP/opioid receptor agonist with full efficacy at NOP and MOP receptors, produces robust analgesic efficacy with reduced adverse effects, conferring promising outcomes in clinical studies. A balanced coactivation of NOP and MOP receptors is a strategy that warrants further exploration and refinement for the development of novel analgesics with a safer and effective profile.

2022-06-01·CNS Drugs

Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation

Review

作者: Rullo, Laura ; Billeci, Domenico ; Scerpa, Maria Sole ; Losapio, Loredana Maria ; Coluzzi, Flaminia ; Romualdi, Patrizia ; Candeletti, Sanzio ; Rocco, Monica

Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.

2022-01-01·European Journal of Pharmacology3区 · 医学

Research progress on the potential novel analgesic BU08028

3区 · 医学

Review

作者: Li, Hongwu ; Shi, Fuqiang ; Guo, Zhihua ; Qin, Di ; Ciccocioppo, Roberto ; Wang, Ya ; Cannella, Nazzareno

Pain is a common symptom accompanying several clinical conditions and causes serious distress to patients. Addressing pain management is an important aspect of disease treatment, including cancer therapy. Opioid analgesics used to manage pain in human and veterinary medicine have been associated with substance dependence and other adverse effects, thereby limiting their application. Thus, the development of opioid analgesics with good safety profiles with minimal adverse effects and no addictive effects, is presently the focus of pain research. As a new potential analgesic, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028) has fewer adverse effects than other analgesics and is expected to be a safer alternative. In this review, we discuss the development of the opioid analog BU08028 and summarize its analgesic effects and biological characteristics, including efficiency, safety, and tolerance. Furthermore, we elaborate on studies showing the bifunctional effect of BU08028, which targets both mu opioid peptide and nociceptin-orphanin FQ peptide receptors, as well as the unique advantages of using BU08028 over single-target opioid agonists. Previous studies have suggested that BU08028 can not only weaken the reward and abuse effects of opioids and other drugs, but also enhance the anti-nociceptive effect of the mu opioid peptide receptors, making it a potent analgesic. Besides, we describe studies suggesting that BU08028 inhibits the effects of alcohol, making it a candidate drug for the management of alcohol addiction. Our review suggests that BU08028 is a potential novel medicine for managing pain and addiction.

100 项与 BU-08028 相关的药物交易

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