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Research ArticleNEUROPHARMACOLOGY

Comparison of Pharmacological Activities of Buprenorphine and Norbuprenorphine: Norbuprenorphine Is a Potent Opioid Agonist

Peng Huang, George B. Kehner, Alan Cowan and Lee-Yuan Liu-Chen
Journal of Pharmacology and Experimental Therapeutics May 2001, 297 (2) 688-695;
Peng Huang
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George B. Kehner
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Alan Cowan
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Lee-Yuan Liu-Chen
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Abstract

Buprenorphine (BUP) is an oripavine analgesic that is beneficial in the maintenance treatment of opiate-dependent individuals. Although BUP has been studied extensively, relatively little is known about norbuprenorphine (norBUP), a major dealkylated metabolite of BUP. We now describe the binding of norBUP to opioid and nociceptin/orphanin FQ (ORL1) receptors, and its effects on [35S]guanosine-5′-O-(γ-thio)triphosphate ([35S]GTPγS) binding mediated by opioid or ORL1 receptors and in the mouse acetic acid writhing test. Chinese hamster ovary cells stably transfected with each receptor were used for receptor binding and [35S]GTPγS binding. NorBUP exhibited high affinities for μ-, δ-, and κ-opioid receptors withK i values in the nanomolar or subnanomolar range, comparable to those of BUP. NorBUP and BUP had low affinities for the ORL1 receptor with K i values in the micromolar range. In the [35S]GTPγS binding assay, norBUP displayed characteristics distinct from BUP. At the δ-receptor, norBUP was a potent full agonist, yet BUP had no agonist activity and antagonized actions of norBUP and DPDPE. At μ- and κ-receptors, both norBUP and BUP were potent partial agonists, with norBUP having moderate efficacy and BUP having low efficacy. At the ORL1 receptor, norBUP was a full agonist with low potency, while BUP was a potent partial agonist. In the writhing test, BUP and norBUP both suppressed writhing in an efficacious and dose-dependent manner, giving A50 values of 0.067 and 0.21 mg/kg, s.c., respectively. These results highlight the similarities and differences between BUP and norBUP, each of which may influence the unique pharmacological profile of BUP.

Footnotes

  • Send reprint requests to: Dr. Lee-Yuan Liu-Chen, Department of Pharmacology, Temple University School of Medicine, 3420 N. Broad St., Philadelphia, PA 19140. E-mail: lliuche{at}astro.temple.edu

  • This work was supported in part by grants from the National Institute on Drug Abuse (DA04745, DA11263, DA13429, and T32 DA07237).

  • Abbreviations:
    BUP
    buprenorphine
    norBUP
    norbuprenorphine
    ORL1
    nociceptin/orphanin FQ receptor
    [35S]GTPγS
    [35S]guanosine-5′-O-(3-thio)triphosphate
    DAMGO
    Tyr-d-Ala-Gly-N-(Me)Phe-Gly-ol
    DPDPE
    Tyr-d-Pen-Gly-Phe-d-Pen-OH (disulfide bridge between d-Pen2 andd-Pen5)
    CHO cell
    Chinese hamster ovary cell
    (−)-U50,488H
    (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidiny)-cyclohexyl]benzeneacetamide methanesulfonate
    N/OFQ
    nociceptin/orphanin FQ
    BSA
    bovine serum albumin
    • Received October 5, 2000.
    • Accepted January 17, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 297 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 297, Issue 2
1 May 2001
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Research ArticleNEUROPHARMACOLOGY

Comparison of Pharmacological Activities of Buprenorphine and Norbuprenorphine: Norbuprenorphine Is a Potent Opioid Agonist

Peng Huang, George B. Kehner, Alan Cowan and Lee-Yuan Liu-Chen
Journal of Pharmacology and Experimental Therapeutics May 1, 2001, 297 (2) 688-695;

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Research ArticleNEUROPHARMACOLOGY

Comparison of Pharmacological Activities of Buprenorphine and Norbuprenorphine: Norbuprenorphine Is a Potent Opioid Agonist

Peng Huang, George B. Kehner, Alan Cowan and Lee-Yuan Liu-Chen
Journal of Pharmacology and Experimental Therapeutics May 1, 2001, 297 (2) 688-695;
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