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Issue 8, 2007
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Opioid ligands with mixed properties from substituted enantiomeric N-phenethyl-5-phenylmorphans. Synthesis of a µ-agonist δ-antagonist and δ-inverse agonists

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Abstract

Enantiomeric N-phenethyl-m-hydroxyphenylmorphans with various substituents in the ortho, meta or para positions of the aromatic ring in the phenethylamine side-chain (chloro, hydroxy, methoxy, nitro, methyl), as well as a pyridylethyl and a indolylethyl moiety on the nitrogen atom, were synthesized and their binding affinity to the µ-, δ-, and κ-opioid receptors was examined. The higher affinity ligands were further examined in the [35S]GTPγS assay to study their function and efficacy. 3-((1R,5S)-(−)-2-(4-Nitrophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((−)-10m) was found to be a µ-agonist and δ-antagonist in that functional assay and was about 50 fold more potent than morphine in vivo. 3-((1R,5S)-(−)-2-(4-Chlorophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((−)-10i) and several other ligands displayed inverse agonist activity at the δ-opioid receptor. The absolute configuration of all of the reported compounds was established by chemical conversion of (−)-6 to 1R,5S-(−)-8b·HBr.

Graphical abstract: Opioid ligands with mixed properties from substituted enantiomeric N-phenethyl-5-phenylmorphans. Synthesis of a µ-agonist δ-antagonist and δ-inverse agonists

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Publication details

The article was received on 02 Jan 2007, accepted on 31 Jan 2007 and first published on 01 Mar 2007


Article type: Paper
DOI: 10.1039/B618875C
Citation: Org. Biomol. Chem., 2007,5, 1177-1190
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    Opioid ligands with mixed properties from substituted enantiomeric N-phenethyl-5-phenylmorphans. Synthesis of a µ-agonist δ-antagonist and δ-inverse agonists

    K. Cheng, I. J. Kim, M. Lee, S. A. Adah, T. J. Raymond, E. J. Bilsky, M. D. Aceto, E. L. May, L. S. Harris, A. Coop, C. M. Dersch, R. B. Rothman, A. E. Jacobson and K. C. Rice, Org. Biomol. Chem., 2007, 5, 1177
    DOI: 10.1039/B618875C

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