Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible μ opioid receptor antagonist effects

Humphrey A. Moynihan, Ian Derrick, Jillian H. Broadbear, Benjamin M. Greedy, Mario D. Aceto, Louis S. Harris, Lauren C.S. Purington, Mark P. Thomas, James H. Woods, John R. Traynor, Stephen M. Husbands, John W. Lewis

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5 Citations (Scopus)

Abstract

We have previously shown that cinnamoyl derivatives of 14β-amino-17- cyclopropylmethyl-7,8-dihydronormorphinone and 7α-aminomethyl-6,14- endoethanonororipavine have pronounced pseudoirreversible μ opioid receptor (MOR) antagonism. The present communication describes the synthesis and evaluation of fumaroylamino analogues of these cinnamoylamino derivatives together with some related fumaroyl derivatives. The predominant activity of the new ligands was MOR antagonism. The fumaroylamino analogues (2a, 5a) of the pseudoirreversible antagonist cinnamoylamino morphinones and oripavines (2b, 5b) were themselves irreversible antagonists in vivo. However the fumaroylamino derivatives had significantly higher MOR efficacy than the cinnamoylamino derivatives in mouse antinociceptive tests. Comparison of 2a and 5a with the prototypic fumaroylamino opioid β-FNA (1a) shows that they have similar MOR irreversible antagonist actions but differ in the nature of their opioid receptor agonist effects; 2a is a predominant MOR agonist and 5a shows no opioid receptor selectivity, whereas the agonist effect of β-FNA is clearly κ opioid receptor (KOR) mediated.

Original languageEnglish
Pages (from-to)9868-9874
Number of pages7
JournalJournal of Medicinal Chemistry
Volume55
Issue number22
Early online date31 Oct 2012
DOIs
Publication statusPublished - 26 Nov 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Moynihan, H. A., Derrick, I., Broadbear, J. H., Greedy, B. M., Aceto, M. D., Harris, L. S., Purington, L. C. S., Thomas, M. P., Woods, J. H., Traynor, J. R., Husbands, S. M., & Lewis, J. W. (2012). Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible μ opioid receptor antagonist effects. Journal of Medicinal Chemistry, 55(22), 9868-9874. https://doi.org/10.1021/jm301096s