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    Synthesis and biological evaluation of dynorphin analogs and, Caco-2 permeability of opioid macrocyclic tetrapeptides

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    Issue Date
    2013-08-31
    Author
    Joshi, Anand Anant
    Publisher
    University of Kansas
    Format
    271 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Medicinal Chemistry
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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    Abstract
    We are interested in the development of potent and highly selective dynorphin (Dyn) analogs targeting kappa opioid receptors (KOR) and studying the pharmacokinetic and physicochemical properties of kappa opioid peptides. In contrast to the extensive structure-activity relationships (SAR) studies on Dyn A, there is minimal SAR information on Dyn B. Therefore we performed an alanine scan of Dyn B amide. The results indicated that Tyr1 and Phe4 residues are critical, while Arg7 is important for maintaining the KOR affinity of Dyn B amide. There is also minimal SAR information for the selective KOR antagonist zyklophin [Nα-benzylTyr1-cyclo(D-Asp5,Dap8)]Dyn A(1-11)NH2 which is active in vivo after systemic administration. Hence, we synthesized linear and cyclic zyklophin analogs using solid phase peptide synthesis. To synthesize cyclic analogs the 5-11 linear fragments were selectively deprotected and cyclized, followed by extension of the peptide chain, coupling of the N-terminal N-alkyl amino acids and cleavage from the resin. We modified a key synthetic step to avoid potential racemization of the N-terminal residue. Pharmacological results suggested that the residue in position 5 has a greater influence on the KOR affinity of zyklophin than the residue in position 8. While Phe4 and Arg6 residues in zyklophin were important for maintaining KOR affinity, surprisingly Tyr1 and Arg7 were not important. The natural product CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) and its D-Trp isomer exhibited KOR activity after oral administration. Therefore, we are investigating the pharmacokinetic and physicochemical properties of these lead peptides. In Caco-2 cell monolayer permeability studies the D-Trp isomer exhibited 7-fold higher permeability in the apical to basolateral direction than CJ-15,208, and the natural product appeared to be an efflux substrate. The permeability of the D-Trp isomer was only 2-fold lower than that of the high permeability compound caffeine. We also examined various agents to solubilize these hydrophobic peptides that are compatible with in vivo studies. The D-Trp isomer had 5- to 40-fold higher solubility than the L-Trp isomer irrespective of the type of solubilizing enhancer used. These studies will help guide the future design of peptidic KOR ligands.
    URI
    http://hdl.handle.net/1808/14842
    Collections
    • Dissertations [4475]
    • Medicinal Chemistry Dissertations and Theses [80]

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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
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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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