Very long-acting narcotic antagonists: The 14β-p-substituted cinnamoylaminomorphinones and their partial mu agonist codeinone relatives

M. D. Aceto, E. R. Bowman, E. L. May, L. S. Harris, J. H. Woods, C. B. Smith, F. Medzihradsky, A. E. Jacobson

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

The biological activity of 14β-(p-halo and p-methylcinnamoylamino)-7,8-dihydro-N-cyclopropylmethylnorcodeinones and their corresponding morphinones was investigated. In vitro, the codeinones displayed predominantly mu agonist activity in the 3H-etorphine binding assay and mouse vas deferens preparation. In vivo, in the mouse, the compounds showed weak to inactive antinociception in the tail-flick and hot-plate tests; however, they were potent agonists in the phenylquinone test and moderately weak antagonists in the tail-flick vs morphine test. They also substituted for morphine in withdrawn morphine-dependent rhesus monkeys. When given to non-withdrawn morphine-dependent monkeys, the codeinones precipitated a delayed but long-lasting withdrawal syndrome. They all generalized to codeine in the drug-discrimination test in rhesus monkeys and, in the dose range tested, two compounds were self-administered. This activity is consistent with that of a partial mu agonist. On the other hand, all the morphinones had very long-acting and highly potent mu antagonist properties. The data can be reconciled by assuming that the codeinones are partially metabolized to their respective morphinones. These compounds may be especially useful in the treatment of opioid dependence.

Original languageEnglish (US)
Pages (from-to)570-575
Number of pages6
JournalArzneimittel-Forschung/Drug Research
Volume39
Issue number5
StatePublished - 1989
Externally publishedYes

ASJC Scopus subject areas

  • Drug Discovery

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