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    Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin

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    Issue Date
    2015-11-25
    Author
    Joshi, Anand Anant
    Murray, Thomas F.
    Aldrich, Jane V.
    Publisher
    American Chemical Society
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    Per SHERPA/RoMEO 4/18/2017: Author's Pre-print: grey tick subject to Restrictions below, author can archive pre-print (ie pre-refereeing) Restrictions: Must obtain written permission from Editor Must not violate ACS ethical Guidelines Author's Post-print: grey tick subject to Restrictions below, author can archive post-print (ie final draft post-refereeing) Restrictions: If mandated by funding agency or employer/ institution If mandated to deposit before 12 months, must obtain waiver from Institution/Funding agency or use AuthorChoice 12 months embargo Publisher's Version/PDF: cross author cannot archive publisher's version/PDF General Conditions: On author's personal website, pre-print servers, institutional website, institutional repositories or subject repositories Non-Commercial Must be accompanied by set statement (see policy) Must link to publisher version Publisher's version/PDF cannot be used
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    Abstract
    The dynorphin (Dyn) A analog zyklophin ([N-benzyl-Tyr1-cyclo(D-Asp5,Dap8)]dynorphin A(1-11)NH2) is a kappa opioid receptor (KOR) selective antagonist in vitro, is active in vivo and antagonizes KOR in the CNS after systemic administration. Hence, we synthesized zyklophin analogs to explore the structure-activity relationships of this peptide. The synthesis of selected analogs required modification to introduce the N-terminal amino acid due to poor solubility and/or to avoid epimerization of this residue. Among the N-terminal modifications the N-phenethyl and the N-cyclopropylmethyl substitutions resulted in the analogs with the highest KOR affinities. Pharmacological results for the alanine-substituted analogs indicated that Phe4 and Arg6, but interestingly not the Tyr1, phenol are important for zyklophin’s KOR affinity, and Arg7 was important for KOR antagonist activity. In the GTPγS assay while all of the cyclic analogs exhibited negligible KOR efficacy, the N-phenethyl-Tyr1, N-CPM-Tyr1 and the N-benzyl-Phe1 analogs were 8- to 24-fold more potent KOR antagonists than zyklophin.
    URI
    http://hdl.handle.net/1808/23730
    DOI
    https://doi.org/10.1021/jm501827k
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    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Joshi, A. A., Murray, T. F., & Aldrich, J. V. (2015). Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin. Journal of Medicinal Chemistry, 58(22), 8783–8795. http://doi.org/10.1021/jm501827k

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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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