Clocinnamox: A novel, systemically-active, irreversible opioid antagonist

S. D. Comer, T. F. Burke, J. W. Lewis, J. H. Woods

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

The warm water (55°C) tail-withdrawal procedure was used to assess the analgesic effects of the prototypic μ opioid agonists, morphine and fentanyl, in mice. Both drugs produced full analgesic effects under these conditions, which were dose-dependently antagonized by naltrexone. The pA2 values for naltrexone with morphine and with fentanyl were not significantly different. Low doses (e.g., 0.32 mg/kg) of clocinnamox [C-CAM · 14β-(p- chlorocinnamoylamino)-7,8-dihydro-N-cyclopropylmethylnormorphinone mesylate] produced rightward shifts in the dose-effect curves for each drug, whereas high doses (e.g., 32 mg/kg) depressed the maximal analgesic response. In addition, it was observed that higher doses of C-CAM were required to produce a shift down in the fentanyl dose-effect curve than were required to produce a shift down in the morphine dose-effect curve, which suggests that fentanyl is more efficacious than morphine. The highest dose of C-CAM (32 mg/kg) antagonized the analgesic effect of morphine for up to 8 days. In contrast, the antagonist activity of naltrexone (100 mg/kg) against morphine lasted for only 2 days. Finally, when naloxone was administered simultaneously with 32 mg/kg C-CAM 2 days before determination of the morphine dose-effect function, the antagonist effect of C-CAM was prevented in a dose-dependent manner. Taken together, these results suggest that C-CAM may be producing its antagonist action at opioid receptors through a nonequilibrium mechanism.

Original languageEnglish (US)
Pages (from-to)1051-1056
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume262
Issue number3
StatePublished - 1992
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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