Differential influence of N-dealkylation on the stimulus properties of some opioid agonists

A. J. Bertalmio, F. Medzihradsky, G. Winger, J. H. Woods

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


The capacity of several opioid agonists and their N-dealkylated derivatives (normetabolites) to substitute for the discriminative and reinforcing stimulus properties of codeine was evaluated in rhesus monkeys, and the affinity of these compounds in binding to mu receptors in rhesus monkey brain membranes was determined. Heroin (0.1 mg/kg), 6-acetylmorphine (0.1 mg/kg), methadone (0.6 mg/kg), 3-acetylmorphine (1 mg/kg), morphine (1 mg/kg) and codeine (1.8 mg/kg) substituted for the codeine cue, but the normetabolites of heroin, 6-acetylmorphine, morphine and codeine did not (up to 10 mg/kg). l-α-Acetylmethadol (3 mg/kg) and its mono (0.1 mg/kg) and double (0.6 mg/kg) N-dealkylated derivatives all substituted. In self administration, subjects responded for morphine (0.1 mg/kg/injection) and codeine (0.3 mg/kg/injection), but not for norcodeine (up to 1 mg/kg/injection) or normorphine (up to 3 mg/kg/injection). l-α- Acetylmethadol (up to 0.3 mg/kg/injection) did not maintain responding, but its mono (0.1 mg/kg/injection) and double (0.1 mg/kg/injection) normetabolites did. In receptor binding, the normetabolites of morphine and 6-acetylmorphine were less potent than their parent agonists in displacing [3H]Tyr-D-Ala-Gly-(Me)Phe-Gly-ol, but the normetabolites of l-α- acetylmethadol had greater affinity than their parent. Codeine and norcodeine were inactive in binding. If l-α-acetylmethadol is converted only slowly to its active normetabolites, this may explain the lack of efficacy found with this compound in the self administration procedure.

Original languageEnglish (US)
Pages (from-to)278-284
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 1992
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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