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

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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 (US)
Pages (from-to)9868-9874
Number of pages7
JournalJournal of Medicinal Chemistry
Volume55
Issue number22
DOIs
StatePublished - Nov 26 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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