Opioid affinity and selectivity of 4-hydroxy-3-methoxyindolomorphinan analogues related to naltrindole

Andrew Coop, Richard B. Rothman, Christina Dersch, John Partilla, Frank Porreca, Peg Davis, Arthur E. Jacobson, Kenner C. Rice

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37 Scopus citations


To investigate the effect of the introduction of a 4-phenolic substituent on the δ opioid affinity and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for all three opioid receptors (μ, κ, δ), 17-cyclopropylmethyl-6,7-didehydro-4-hydroxy-3-methoxy-6,7:2',3'- indolomorphinan (13) was an exception, displaying excellent 5 binding selectivity (δ K(i) = 7 nM, μ/δ = 1900, μ/κ = 1130). GTP-χ-S functional assays showed 13 to be a selective δ antagonist, albeit with lower potency than naltrindole. Although the reason for the unique profile of 13 could not be determined, these results validate our approach of introducing groups into the indolomorphinans that are known to reduce μ activity, to obtain increased δ selectivity.

Original languageEnglish (US)
Pages (from-to)1673-1679
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - May 6 1999

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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