BU 08073 a buprenorphine analogue with partial agonist activity at μ‐receptors in vitro but long‐lasting opioid antagonist activity in vivo in mice
Open accessAbstract
BACKGROUND AND PURPOSE: Buprenorphine is a potent analgesic with high affinity at μ, δ and κ and moderate affinity at nociceptin opioid (NOP) receptors. Nevertheless, NOP receptor activation modulates the in vivo activity of buprenorphine. Structure activity studies were conducted to design buprenorphine analogues with high affinity at each of these receptors and to characterize them in in vitro and in vivo assays. EXPERIMENTAL APPROACH: Compounds were tested for binding affinity and functional activity using [(35) S]GTPγS binding at each receptor and a whole-cell fluorescent assay at μ receptors. BU08073 was evaluated for antinociceptive agonist and antagonist activity and for its effects on anxiety in mice. KEY RESULTS: BU08073 bound with high affinity to all opioid receptors. It had virtually no efficacy at δ, κ and NOP receptors, whereas at μ receptors, BU08073 has similar efficacy as buprenorphine in both functional assays. Alone, BU08073 has anxiogenic activity and produces very little antinociception. However, BU08073 blocks morphine and U50,488-mediated antinociception. This blockade was not evident at 1 h post-treatment, but is present at 6 h and remains for up to 3-6 days. CONCLUSIONS AND IMPLICATIONS: These studies provide structural requirements for synthesis of 'universal' opioid ligands. BU08073 had high affinity for all the opioid receptors, with moderate efficacy at μ receptors and reduced efficacy at NOP receptors, a profile suggesting potential analgesic activity. However, in vivo, BU08073 had long-lasting antagonist activity, indicating that its pharmacokinetics determined both the time course of its effects and what receptor-mediated effects were observed. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
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Buprenorphine is a mu-opioid receptor partial agonist and a kappa/delta-opioid receptor antagonist; it binds with high affinity to mu and kappa receptors and with lower affinity to delta receptors.
“Pharmacodynamic notions: BUP is a MOR partial agonist and a KOR/DOR antagonist; it binds with a high affinity to MOR and KOR, and it binds with a lower affinity to DOR [35].”
From The Efficacy of Buprenorphine in Major Depression, Treatment-Resistant Depression and Suicidal Behavior: A Systematic Review (2018) · cites this paper as [35]
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- Authors
- Khroyan, T. V., Wu, J., Polgar, W. E., Cami‐Kobeci, G., Fotaki, N., Husbands, S. M., & Toll, L.
- Affiliations
- SRI International (US)
- Torrey Pines Institute For Molecular Studies (US)
- University of Bath (GB)
- Corresponding author
- Husbands, S M
- Toll, L
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2014-11-05
- Volume
- 172
- Issue
- 2
- Pages
- 668-680
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC4292977
- OpenAlex
- W2171087382
- Cited by
- 40
- References
- 64
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 6 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 8 · 2017: 1 · 2016: 5 · 2015: 1
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- British Journal of Pharmacology (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure (University of Bath) (submittedVersion, cc-by-nc)
- University of Bedfordshire Repository (University of Bedfordshire) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute on Drug Abuse (DA023281, DA20469)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- opioid receptor affinity, mu-opioid receptor, delta opioid receptor, kappa opioid receptor, antinociception, morphine antagonism, U50,488, anxiogenic activity, structure-activity relationship, pharmacokinetics
- MeSH terms
- Analgesics, Opioid, Animals, Anxiety, Behavior, Animal, Buprenorphine, Cricetulus, Hot Temperature, Humans, Male, Membrane Potentials, Mice, Inbred ICR, Narcotic Antagonists, Pain, CHO Cells, Receptors, Opioid, mu, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
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