KUKU

KU ScholarWorks

  • myKU
  • Email
  • Enroll & Pay
  • KU Directory
    • Login
    View Item 
    •   KU ScholarWorks
    • Dissertations and Theses
    • Theses
    • View Item
    •   KU ScholarWorks
    • Dissertations and Theses
    • Theses
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands

    Thumbnail
    View/Open
    Johnson_ku_0099M_15233_DATA_1.pdf (12.47Mb)
    Issue Date
    2017-05-31
    Author
    Johnson, Stephanie
    Publisher
    University of Kansas
    Format
    277 pages
    Type
    Thesis
    Degree Level
    M.S.
    Discipline
    Medicinal Chemistry
    Rights
    Copyright held by the author.
    Metadata
    Show full item record
    Abstract
    The ability of ligands to differentially regulate the activity of signaling pathways coupled to a receptor potentially enables researchers to optimize therapeutically relevant efficacies, while minimizing activity at pathways that lead to adverse effects. Recent studies have demonstrated the functional selectivity of kappa opioid receptor (KOR) ligands acting at KOR expressed by rat peripheral pain sensing neurons. In addition, KOR signaling leading to antinociception and dysphoria occur via different pathways. Based on this information, it can be hypothesized that a functionally selective KOR agonist would allow researchers to optimize signaling pathways leading to antinociception while simultaneously minimizing activity towards pathways that result in dysphoria. In this study, our goal was to alter the structure of U50,488 such that efficacy was maintained for signaling pathways important for antinociception (inhibition of cAMP accumulation) and minimized for signaling pathways that reduce antinociception. Thus, several compounds based on the U50,488 scaffold were designed, synthesized, and evaluated at KORs. Selected analogues were further evaluated for inhibition of cAMP accumulation, activation of extracellular signal-regulated kinase (ERK), and inhibition of calcitonin gene-related peptide release (CGRP). The data obtained demonstrates that modification of the structure of U50,488 changed the signaling pathway regulation. Specifically, we identified three functionally selective KOR ligands (4b, 9u, and 9ac) that inhibit cAMP accumulation, similar to U50,488, but, unlike U50,488, do not activate ERK. In addition, the ability to inhibit CGRP release showed monotonic concentration-response curves, indicating that a pathway leading to nociception is not activated. These data suggest that the efficacy for specific signaling pathways can be finely tuned by structural modifications to a given ligand.
    URI
    http://hdl.handle.net/1808/26154
    Collections
    • Medicinal Chemistry Dissertations and Theses [81]
    • Theses [3824]

    Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.


    We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.


    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
     

     

    Browse

    All of KU ScholarWorksCommunities & CollectionsThis Collection

    My Account

    LoginRegister

    Statistics

    View Usage Statistics

    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
     

     

    The University of Kansas
      Contact KU ScholarWorks
    Lawrence, KS | Maps
     
    • Academics
    • Admission
    • Alumni
    • Athletics
    • Campuses
    • Giving
    • Jobs

    The University of Kansas prohibits discrimination on the basis of race, color, ethnicity, religion, sex, national origin, age, ancestry, disability, status as a veteran, sexual orientation, marital status, parental status, gender identity, gender expression and genetic information in the University’s programs and activities. The following person has been designated to handle inquiries regarding the non-discrimination policies: Director of the Office of Institutional Opportunity and Access, IOA@ku.edu, 1246 W. Campus Road, Room 153A, Lawrence, KS, 66045, (785)864-6414, 711 TTY.

     Contact KU
    Lawrence, KS | Maps