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Research ArticleBehavioral Pharmacology

Preclinical Pharmacology of AZD2327: A Highly Selective Agonist of the δ-Opioid Receptor

T. J. Hudzik, C. Maciag, M. A. Smith, R. Caccese, M. R. Pietras, K. H. Bui, M. Coupal, L. Adam, K. Payza, A. Griffin, G. Smagin, D. Song, M. D. B. Swedberg and W. Brown
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 195-204; DOI: https://doi.org/10.1124/jpet.111.179432
T. J. Hudzik
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C. Maciag
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M. A. Smith
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R. Caccese
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M. R. Pietras
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K. H. Bui
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M. Coupal
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L. Adam
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K. Payza
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A. Griffin
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G. Smagin
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D. Song
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M. D. B. Swedberg
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W. Brown
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Abstract

In the present article, we summarize the preclinical pharmacology of 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)-piperazin-1-yl]methyl}-N,N-diethylbenzamide (AZD2327), a highly potent and selective agonist of the δ-opioid receptor. AZD2327 binds with sub-nanomolar affinity to the human opioid receptor (Ki = 0.49 and 0.75 nM at the C27 and F27 isoforms, respectively) and is highly selective (>1000-fold) over the human μ- and κ-opioid receptor subtypes as well as >130 other receptors and channels. In functional assays, AZD2327 shows full agonism at human δ-opioid receptors ([35S]GTPγ EC50 = 24 and 9.2 nM at C27 and F27 isoforms, respectively) and also at the rat and mouse δ-opioid receptors. AZD2327 is active in a wide range of models predictive of anxiolytic activity, including a modified Geller-Seifter conflict test and social interaction test, as well as in antidepressant models, including learned helplessness. In animals implanted with microdialysis probes and then given an acute stressor by pairing electric shock delivery with a flashing light, there is an increase in norepinephrine release into the prefrontal cortex associated with this acute anxiety state. Both the benzodiazepine anxiolytic standard diazepam and AZD2327 blocked this norepinephrine release equally well, and there was no evidence of tolerance to these effects of AZD2327. Overall, these data support the role of the δ-opioid receptor in the regulation of mood, and data suggest that AZD2327 may possess unique antidepressant and anxiolytic activities that could make a novel contribution to the pharmacotherapy of psychiatric disorders.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.179432.

  • ABBREVIATIONS:

    FK 33-824
    Met-enkephalin
    AZD2327
    4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)-piperazin-1-yl]methyl}-N,N-diethylbenzamide
    AR-M100390
    N,N-diethyl-4-[phenyl(piperidin-4-ylidene)methyl]benzamide
    ADL5747
    [N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4'-piperidine]-4-yl)benzamide]
    SNC-80
    4-[(R)-[(2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl]-(3-methoxyphenyl)methyl]-N,N-diethyl-benzamide
    DPDYN
    d-Pro10-dynorphin A(1-11)
    U69593
    N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]acetamide
    NE
    norepinephrine
    MHPG
    3-methoxy-4-hydroxyphenolglycol
    ANOVA
    analysis of variance
    PTZ
    pentylenetetrazole
    ADL5859
    N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4′-piperidin]-4-yl)benzamide
    HEK
    human embryonic kidney.

  • Received January 18, 2011.
  • Accepted March 24, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleBehavioral Pharmacology

Preclinical Pharmacology of AZD2327: A Highly Selective Agonist of the δ-Opioid Receptor

T. J. Hudzik, C. Maciag, M. A. Smith, R. Caccese, M. R. Pietras, K. H. Bui, M. Coupal, L. Adam, K. Payza, A. Griffin, G. Smagin, D. Song, M. D. B. Swedberg and W. Brown
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 195-204; DOI: https://doi.org/10.1124/jpet.111.179432

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Research ArticleBehavioral Pharmacology

Preclinical Pharmacology of AZD2327: A Highly Selective Agonist of the δ-Opioid Receptor

T. J. Hudzik, C. Maciag, M. A. Smith, R. Caccese, M. R. Pietras, K. H. Bui, M. Coupal, L. Adam, K. Payza, A. Griffin, G. Smagin, D. Song, M. D. B. Swedberg and W. Brown
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 195-204; DOI: https://doi.org/10.1124/jpet.111.179432
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