Probes for narcotic receptor-mediated phenomena. 21. Novel derivatives of 3-(1,2,3,4,5,11-hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]indol-6-yl) phenols with improved δ opioid receptor selectivity

Craig M. Bertha, Matthew Ellis, Judith L. Flippen-Anderson, Frank Porreca, Richard B. Rothman, Peg Davis, Heng Xu, Karen Becketts, Kenner C. Rice

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Derivatives of racemic and optically pure levorotatory 3-(1,2,3,4,5,11-hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]indol-6-yl) phenols containing methoxy substituents in the C10′, C9′, and C8′ positions (compounds 9-11, respectively) were synthesized and characterized by spectroscopic and X-ray methods. The binding affinities for the μ, δ, and κ1 opioid receptors and activity in the guinea pig ileum (GPI) and mouse vas deferens (MVD) functional bioassays were determined for these compounds. A methoxy substituent in the C8′ position decreases the binding affinity for both the μ and δ receptors, while a C10′ methoxy substituent has little effect on either binding affinity. Interestingly, a methoxy group at the C9′ position in the levorotatory series provides compound (-)-10 which exhibits both enhanced in vitro affinity and selectivity for the δ opioid receptor relative to the unsubstituted derivative (-)-8 and is the most selective (μ/δ IC50 ratio 17.9, κ1/δ IC50 ratio 314) and highest affinity (IC50 3.7 nM) δ receptor ligand for this novel class of compounds. The results of the GPI and MVD bioassays are more dramatic and indicate that (-)-10 is an agonist for the δ receptor (IC50 49.0 nM) with substantial selectivity for the δ versus the μ receptor borne out by a GPI/MVD IC50 ratio of >612.

Original languageEnglish (US)
Pages (from-to)2081-2086
Number of pages6
JournalJournal of Medicinal Chemistry
Volume39
Issue number10
StatePublished - May 10 1996

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Bioassay
Phenols
Opioid Receptors
Inhibitory Concentration 50
Vas Deferens
Derivatives
Ileum
Guinea Pigs
Biological Assay
Ligands
X rays
X-Rays

ASJC Scopus subject areas

  • Organic Chemistry

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Probes for narcotic receptor-mediated phenomena. 21. Novel derivatives of 3-(1,2,3,4,5,11-hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]indol-6-yl) phenols with improved δ opioid receptor selectivity. / Bertha, Craig M.; Ellis, Matthew; Flippen-Anderson, Judith L.; Porreca, Frank; Rothman, Richard B.; Davis, Peg; Xu, Heng; Becketts, Karen; Rice, Kenner C.

In: Journal of Medicinal Chemistry, Vol. 39, No. 10, 10.05.1996, p. 2081-2086.

Research output: Contribution to journalArticle

Bertha, Craig M. ; Ellis, Matthew ; Flippen-Anderson, Judith L. ; Porreca, Frank ; Rothman, Richard B. ; Davis, Peg ; Xu, Heng ; Becketts, Karen ; Rice, Kenner C. / Probes for narcotic receptor-mediated phenomena. 21. Novel derivatives of 3-(1,2,3,4,5,11-hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]indol-6-yl) phenols with improved δ opioid receptor selectivity. In: Journal of Medicinal Chemistry. 1996 ; Vol. 39, No. 10. pp. 2081-2086.
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AU - Bertha, Craig M.

AU - Ellis, Matthew

AU - Flippen-Anderson, Judith L.

AU - Porreca, Frank

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AU - Davis, Peg

AU - Xu, Heng

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AU - Rice, Kenner C.

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