A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates
Authors
Ding, HuipingCzoty, Paul W.
Kiguchi, Norikazu
Cami-Kobeci, Gerta
Sukhtankar, Devki D.
Nader, Michael A.
Husbands, Stephen M.
Ko, Mei-Chuan
Issue Date
2016-08-29Subjects
respiratory depressionN/ofq peptide receptor
Mu opioid peptide receptor
physical dependence
reinforcing effects
Subject Categories::B200 Pharmacology, Toxicology and Pharmacy
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Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various wellhoned behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ?10-to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abusefree opioid analgesics.Citation
Ding H, Czoty PW, Kiguchi N, Cami-Kobeci G, Sukhtankar DD, Nader MA, Husbands SM, Ko MC (2016) 'A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates', Proceedings of the National Academy of Sciences, 113 (37), pp.E5511-E5518.Publisher
National Academy of SciencesPubMed ID
27573832PubMed Central ID
PMC5027459Additional Links
https://www.pnas.org/content/113/37/E5511.longhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027459/
Type
ArticleLanguage
enISSN
0027-8424ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1605295113
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