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Deletion of Ac-NMePhe1 from [NMePhe1]arodyn under acidic conditions, part 2: Effects of cleavage conditions and N-terminal functionality

Authors

  • Wei-Jie Fang,

    1. Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045
    Current affiliation:
    1. Department of Chemical and Biological Engineering, University of Colorado, Boulder, CO 80309
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  • Marco A. Bennett,

    1. Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201
    Current affiliation:
    1. Food and Drug Administration, Rockville, MD 20855
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  • Jane V. Aldrich

    Corresponding author
    1. Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045
    • Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045
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  • This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Abstract

Peptides containing N-methylamino acids can exhibit improved pharmacodynamic and pharmacokinetic profiles compared to nonmethylated peptides, and therefore interest in these N-methylated peptides has been increasing in recent years. Arodyn (Ac[Phe1,2,3,Arg4,D-Ala8]Dyn A(1–11)NH2) is an acetylated dynorphin A (Dyn A) analog that is a potent and selective κ opioid receptor antagonist (Bennett et al., J Med Chem 2002, 45, 5617), and its analog [NMePhe1]arodyn shows even higher affinity and selectivity for κ opioid receptors (Bennett et al., J Pept Res 2005, 65, 322). During the synthesis of [NMePhe1]arodyn analogs, the arodyn-(2–11) derivatives were obtained as major products. Analysis indicated that Ac-NMePhe was lost from the completed peptide sequence during acidic cleavage of the peptides from the resin and that the acetyl group played an important role in this side reaction. Different cleavage conditions were evaluated to minimize this side reaction and maximize the yield of pure [NMePhe1]arodyn analogs. Modifications to the N-terminus of the peptides to prevent the side reaction were also explored. The incorporation of a heteroatom-containing group such as methoxycarbonyl as the N-terminal functionality prevented this side reaction, while the incorporation of a bulky acyl group could not. Substituting NMePhe with the conformationally constrained analog Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) also prevented the side reaction. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 97–102, 2011.

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