Opioid Agonist and Antagonist Bivalent Ligands. The Relationship between Spacer Length and Selectivity at Multiple Opioid Receptors

Philip S Portoghese, D. L. Larson, L. M. Sayre, C. B. Yim, G. Ronsisvalle, S. W. Tam, A. E. Takemori

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92 Scopus citations

Abstract

Bivalent ligands containing the oxymorphamine or naltrexamine pharmacophores connected to spacers of varying length were synthesized and evaluated for their selectivity at μ, K, and δ opioid receptors. The oxymorphamine bivalent ligands (1–8) behaved as μ agonists on the electrically stimulated guinea pig ileum longitudinal muscle preparation (GPI). The spacer that conferred peak agonist activity in these series contains a total of four glycyl units (n = 2). Binding studies with guinea pig brain membranes showed a qualitatively similar profile at μ receptors as a function of spacer length. Also, δ receptor selectivity increased as the spacer was lengthened. The naltrexamine bivalent ligands (9–13) effectively antagonized the μ receptor agonist morphine in the GPI at the same optimal spacer length (n = 2) as in the agonist series. However, the peak antagonism of ethylketazocine, a k receptor agonist, occurred with the bivalent ligand 9 containing the shortest spacer (n = 0), and it was found that 9 is the most selective k antagonist in the series. While receptor binding roughly parallels that of k antagonist activity in the GPI, no correlation between binding and antagonist activity was observed at μ opioid receptors. The possible significance of these results is discussed.

Original languageEnglish (US)
Pages (from-to)1855-1861
Number of pages7
JournalJournal of medicinal chemistry
Volume29
Issue number10
DOIs
StatePublished - 1986

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