BU74, a complex oripavine derivative with potent kappa opioid receptor agonism and delayed opioid antagonism

Stephen M. Husbands, Claire L. Neilan, Jillian Broadbear, Peter Grundt, Simon Breeden, Mario D. Aceto, James H. Woods, John W. Lewis, John R. Traynor

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

In the search for opioid agonists with delayed antagonist actions as potential treatments for substance abuse, the bridged morphinan BU74 (17-cyclopropylmethyl-3-hydroxy-[5β,7β,3′,5′]-pyrrolidino- 2′[S]-phenyl-7α-methyl-6,14-endoetheno morphinan) (3f) was synthesized. In isolated tissue and [35S]GTPγS opioid receptor functional assays BU74 was shown to be a potent long-lasting kappa opioid receptor agonist, delta opioid receptor partial agonist and mu opioid receptor antagonist. In antinociceptive tests in the mouse, BU74 showed high efficacy and potent kappa opioid receptor agonism. When its agonist action had waned BU74 became an antagonist of kappa and mu opioid receptor agonists in the tail flick assay and of delta, kappa and mu opioid receptor agonists in the acetic acid writhing assay. The slow onset, long-duration kappa opioid receptor agonist effects of BU74 suggests that it could be a lead compound for the discovery of a treatment for cocaine abuse.

Original languageEnglish (US)
Pages (from-to)117-125
Number of pages9
JournalEuropean Journal of Pharmacology
Volume509
Issue number2-3
DOIs
StatePublished - Feb 21 2005
Externally publishedYes

Keywords

  • Antinociception
  • Delayed antagonism
  • Efficacy
  • Kappa-opioid

ASJC Scopus subject areas

  • Pharmacology

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    Husbands, S. M., Neilan, C. L., Broadbear, J., Grundt, P., Breeden, S., Aceto, M. D., Woods, J. H., Lewis, J. W., & R. Traynor, J. (2005). BU74, a complex oripavine derivative with potent kappa opioid receptor agonism and delayed opioid antagonism. European Journal of Pharmacology, 509(2-3), 117-125. https://doi.org/10.1016/j.ejphar.2004.12.035