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BU08073 a buprenorphine analogue with partial agonist activity at μ-receptors in vitro but long-lasting opioid antagonist activity in vivo in mice

  • Gerta Cami-Kobeci
    ,
  • Taline V. Khroyan
    ,
  • J. Wu
    ,
  • Willma E. Polgar
    ,
  • N. Fotaki
    ,
  • Stephen M. Husbands
  • Torrey Pines Institute for Molecular Studies
    ,
  • University of Bath
Research Output: Contribution to journal Article Peer-review

Open access

Abstract

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 [35S]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.

Publication Information

Output type

Research Output: Contribution to journal Article Peer-review

Original language

English

Pages from-to (Number of pages)

Pages 668-680

Journal (Volume, Issue Number)

British Journal of Pharmacology (Volume 172, Issue 2)

Publication milestones

  • Accepted/In press - 25/05/2014
  • Published - 05/06/2014

Publication status

Published - 05/06/2014

ISSN

0007-1188

External Publication IDs

  • handle.net: 10547/624680
  • Scopus: 84920139196

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