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

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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
Volume42
Issue number9
DOIs
StatePublished - May 6 1999

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naltrindole
Opioid Analgesics
Assays
Opioid Receptors
Guanosine Triphosphate
Ligands

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Opioid affinity and selectivity of 4-hydroxy-3-methoxyindolomorphinan analogues related to naltrindole. / Coop, Andrew; Rothman, Richard B.; Dersch, Christina; Partilla, John; Porreca, Frank; Davis, Peg; Jacobson, Arthur E.; Rice, Kenner C.

In: Journal of Medicinal Chemistry, Vol. 42, No. 9, 06.05.1999, p. 1673-1679.

Research output: Contribution to journalArticle

Coop, A, Rothman, RB, Dersch, C, Partilla, J, Porreca, F, Davis, P, Jacobson, AE & Rice, KC 1999, 'Opioid affinity and selectivity of 4-hydroxy-3-methoxyindolomorphinan analogues related to naltrindole', Journal of Medicinal Chemistry, vol. 42, no. 9, pp. 1673-1679. https://doi.org/10.1021/jm9807003
Coop, Andrew ; Rothman, Richard B. ; Dersch, Christina ; Partilla, John ; Porreca, Frank ; Davis, Peg ; Jacobson, Arthur E. ; Rice, Kenner C. / Opioid affinity and selectivity of 4-hydroxy-3-methoxyindolomorphinan analogues related to naltrindole. In: Journal of Medicinal Chemistry. 1999 ; Vol. 42, No. 9. pp. 1673-1679.
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AU - Dersch, Christina

AU - Partilla, John

AU - Porreca, Frank

AU - Davis, Peg

AU - Jacobson, Arthur E.

AU - Rice, Kenner C.

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