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    Identification of a Novel “Almost Neutral” Mu Opioid Receptor Antagonist in CHO Cells Expressing the Cloned Human Mu Opioid Receptor

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    Prisinzano_2010.pdf (568.7Kb)
    Issue Date
    2010-04
    Author
    Sally, Elliott J.
    Xu, Heng
    Dersch, Christina M.
    Hsin, Ling-Wei
    Chang, Li-Te
    Prisinzano, Thomas E.
    Simpson, Denise S.
    Giuvelis, Denise
    Rice, Kenner C.
    Jacobson, Arthur E.
    Cheng, Kejun
    Bilsky, Edward J.
    Rothman, Richard B.
    Publisher
    Wiley
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
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    Abstract
    The basal (constitutive) activity of G protein-coupled receptors allows for the measurement of inverse agonist activity. Some competitive antagonists turn into inverse agonists under conditions where receptors are constitutively active. In contrast, neutral antagonists have no inverse agonist activity, and they block both agonist and inverse agonist activity. The mu opioid receptor (MOR) demonstrates detectable constitutive activity only after a state of dependence is produced by chronic treatment with a MOR agonist. We therefore sought to identify novel MOR inverse agonists, and novel neutral MOR antagonists in both untreated and agonist-treated MOR cells. CHO cells expressing the cloned human mu receptor (hMOR-CHO cells) were incubated for 20 hr with medium (control) or 10 μM (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester (herkinorin, HERK). HERK-treatment generates a high degree of basal signaling and enhances the ability to detect inverse agonists. [35S]-GTP-γ-S assays were conducted using established methods. We screened 21 MOR “antagonists” using membranes prepared from HERK-treated hMOR-CHO cells. All antagonists, including CTAP and 6β-naltrexol, were inverse agonists. However, LTC-2 7 4 ( (-)-3-cyclopropylmethyl-2,3,4,4aα,5,6,7,7aα-octahydro-1H-benzofuro[3,2-e]isoquinolin-9-ol)) showed the lowest efficacy as an inverse agonist, and, at concentrations less than 5 nM, had minimal effects on basal [35S]-GTP-γ-S binding. Other efforts in this study identified KC-2-009 ((+)-3-((1R,5S)-2-((Z)-3-Phenylallyl)-2-azabicyclo[3.3.1]nonan-5-yl)phenol hydrochloride) as an inverse agonist at untreated MOR cells. In HERK-treated cells, KC-2-009 had the highest efficacy as an inverse agonist. In summary, we identified a novel and selective MOR inverse agonist (KC-2-009), and a novel MOR antagonist (LTC-274) that shows the least inverse agonist activity among 21 MOR antagonists. LTC-274 is a promising lead compound for developing a true MOR neutral antagonist.
    Description
    This is the peer reviewed version of the following article: Sally, E. J., Xu, H., Dersch, C. M., Hsin, L.-W., Chang, L.-T., Prisinzano, T. E., Simpson, D. S., Giuvelis, D., Rice, K. C., Jacobson, A. E., Cheng, K., Bilsky, E. J. and Rothman, R. B. (2010), Identification of a novel “almost neutral” μ-opioid receptor antagonist in CHO cells expressing the cloned human μ-opioid receptor. Synapse, 64: 280–288. doi:10.1002/syn.20723, which has been published in final form at http://doi.org/10.1002/syn.20723 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
    URI
    http://hdl.handle.net/1808/24008
    DOI
    https://doi.org/10.1002/syn.20723
    Collections
    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Sally, E. J., Xu, H., Dersch, C. M., Hsin, L.-W., Chang, L.-T., Prisinzano, T. E., Simpson, D. S., Giuvelis, D., Rice, K. C., Jacobson, A. E., Cheng, K., Bilsky, E. J. and Rothman, R. B. (2010), Identification of a novel “almost neutral” μ-opioid receptor antagonist in CHO cells expressing the cloned human μ-opioid receptor. Synapse, 64: 280–288. doi:10.1002/syn.20723

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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