Synthesis and biological evaluation of 14-alkoxymorphinans 21. Novel 4-alkoxy and 14-phenylpropoxy derivatives of the μ opioid receptor antagonist cyprodime

Mariana Spetea, Falko Schüllner, Radu C. Moisa, Ilona P. Berzetei-Gurske, Barbara Schraml, Cynthia Dörfler, Mario D. Aceto, Louis S. Harris, Andrew Coop, Helmut Schmidhammer

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

The synthesis, biological, and pharmacological evaluation of novel derivatives of cyprodime are described. Their binding affinities at μ, δ, and κ opioid receptors were evaluated using receptor binding assay. It was observed that the affinity of these compounds was sensitive to the character and length of the substituent in position 4. Further prolongation of the 4-alkoxy group of cyprodime (1) and its 4-butoxy analogue 2 is detrimental for the μ opioid receptor affinity. Introduction of an arylalkoxy group at C-4 does not increase μ affinity in the case of benzyloxy, while a phenylpropoxy group reduces μ affinity. The δ and κ affinities were also reduced compared to the reference compounds. A significant increase in the affinity at the μ opioid receptors was achieved by introducing a 14-phenylpropoxy group. Increases in the affinity at δ and κ receptors were also observed. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. In the [ 35S]GTPγS binding assay, all tested compounds were partial agonists at μ and δ receptors. Compounds 8 and 17 showed antagonism at κ receptors, while compound 7 exhibited some partial agonist activity at this receptor. The novel derivatives of cyprodime containing a 14-phenylpropoxy group acted as potent antinociceptives. When tested in vivo, compounds 7, 8, and 17 were considerably more potent than morphine, with phenol 7 showing the highest antinociceptive potency (21-fold in the hot plate test, 38-fold in the tail flick test, and 300-fold in the paraphenylquinone writhing test) in mice. Introduction of a 14-phenylpropoxy substituent leads to a profound alteration in the pharmacological profile of this class of compounds.

Original languageEnglish (US)
Pages (from-to)3242-3247
Number of pages6
JournalJournal of Medicinal Chemistry
Volume47
Issue number12
DOIs
StatePublished - Jun 3 2004
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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