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Research ArticleArticle

Ring-Constrained Orvinols as Analogs of Buprenorphine: Differences in Opioid Activity Related to Configuration of C20 Hydroxyl Group

J. R. Traynor, L. Guo, A. Coop, J. W. Lewis and J. H. Woods
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1093-1099;
J. R. Traynor
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L. Guo
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A. Coop
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J. W. Lewis
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J. H. Woods
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Abstract

The relative positions of the C20 substituents in buprenorphine, particularly the hydroxyl group, have been implicated in its actions as a partial μ-agonist and a κ-antagonist. This hypothesis has been examined by the synthesis and pharmacological characterization of five orvinols in which the C20 carbon atom of buprenorphine is constrained in a five-membered ring, fixing the hydroxyl group above (β) or below (α) the plane of the ring. All five compounds were nonselective in binding assays with similar, low nanomolar affinities. The compounds acted as δ-agonists in the mouse vas deferens and κ-agonists in the myenteric plexus-longitudinal muscle of the guinea pig ileum and in Chinese hamster ovary (CHO) cells expressing the human κ-opioid receptor (CHO-hkor). All were lower efficacy μ-agonists than buprenorphine as measured by the [35S]guanosine-5′-O-(3-thio)triphosphate assay in SH-SY5Y cells. The major difference between the isomers was an 11- to 12-fold higher potency of the β-OH isomer (BU46) compared with the α-OH isomer (BU47) at the κ-receptor in the guinea pig ileum and CHO-hkor cells and a somewhat higher efficacy of BU46 in CHO-hkor cells. BU46 and BU47 were evaluated in vivo. BU46 was a full agonist in the mouse writhing assay and antinociception was prevented by norbinaltorphimine, showing a κ-mechanism of action. In contrast, BU47 acted as an antagonist of μ-, δ-, and κ-mediated antinociception in the writhing assay. The results show that the configuration of the hydroxyl group is not important in binding affinity at μ-, δ-, or κ-receptors but does influence κ-potency and κ-efficacy, particularly in vivo.

Footnotes

  • Send reprint requests to: J. R. Traynor, Department of Pharmacology, University of Michigan Medical School, 1301 Medical Science Research Building III, Ann Arbor, MI 48109-0632. E-mail:jtraynor{at}umich.edu

  • ↵1 This work was supported by United States Public Health Service Grants DA-00254 and DA-07315.

  • ↵2 Current address: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201.

  • Abbreviations:
    BU46
    N-cyclopropylmethyl-[7α,8α,2′,3′]-cyclopentano-1′[R]-hydroxy-6,14-endo-ethenotetrahydronororipavine
    BU47
    N-cyclopropylmethyl-[7α,8α,2′,3′]-cyclopentano-1′[S]-hydroxy-6,14-endo-ethenotetrahydronororipavine
    GTPγS
    guanosine-5′-O-(3-thio)triphosphate
    DPDPE
    [d-Pen2,d-Pen5]enkephalin
    DAMGO
    [d-Ala2,MePhe4,Gly-ol5]enkephalin
    [H3]CI977
    5R-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-4-benzofuranacetamide
    U69593
    5α,7α,8β-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-benzeneacetamide
    NTI
    naltrindole
    norBNI
    norbinaltorphimine
    M-CAM
    methocinnamox
    SNC80
    (+)4-[(α-R)-α-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-methoxybenzyl]-N,N-dimethylbenzamide
    IR
    infrared
    MVD
    mouse vas deferens
    GPI
    guinea pig ileum
    CHO
    Chinese hamster ovary
    CHO-hkor
    CHO cells expressing the human κ-opioid receptor
    • Received February 26, 1999.
    • Accepted August 6, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Ring-Constrained Orvinols as Analogs of Buprenorphine: Differences in Opioid Activity Related to Configuration of C20 Hydroxyl Group

J. R. Traynor, L. Guo, A. Coop, J. W. Lewis and J. H. Woods
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1093-1099;

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Research ArticleArticle

Ring-Constrained Orvinols as Analogs of Buprenorphine: Differences in Opioid Activity Related to Configuration of C20 Hydroxyl Group

J. R. Traynor, L. Guo, A. Coop, J. W. Lewis and J. H. Woods
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1093-1099;
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