Synthesis and biological evaluation of 14-alkoxymorphinans. 18.1 N-substituted 14-phenylpropyloxymorphinan-6-ones with unanticipated agonist properties: Extending the scope of common structure-activity relationships

Elisabeth Greiner, Mariana Spetea, Roland Krassnig, Falko Schüllner, Mario Aceto, Louis S. Harris, John R. Traynor, James H. Woods, Andrew Coop, Helmut Schmidhammer

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

The synthesis, biological, and pharmacological evaluations of 14β-O-phenylpropyl-substituted morphinan-6-ones are described. The most striking finding of this study was that all of the compounds from the novel series of differently N-substituted 14β-O-phenylpropylmorphinans acted as powerful opioid agonists. Even with N-substituents such as cyclopropylmethyl and allyl, which are usually associated with distinct antagonist properties, only agonists were obtained. Compared to morphine, the N-cyclopropylmethyl derivative 15 showed considerably increased potency in the in vivo assays in mice (600-fold in the tail-flick assay, 60-fold in the paraphenylquinone writhing test, and 400-fold in the hot-plate assay). Remarkably, most of the new ligands were nonselective and exhibited binding affinities in the subnanomolar range at opioid receptors (μ, κ, δ), with the N-propyl derivative 19 displaying the highest affinity for the μ-receptor (Ki = 0.09 nM).

Original languageEnglish (US)
Pages (from-to)1758-1763
Number of pages6
JournalJournal of Medicinal Chemistry
Volume46
Issue number9
DOIs
StatePublished - Apr 24 2003
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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