Deletion of Ac-NMePhe(1) from [NMePhe(1) ]arodyn under acidic conditions, part 2: effects of substitutions on pharmacological activity.

Wei Jie Fang, Marco A. Bennett, Thomas F. Murray, Jane V. Aldrich

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Arodyn (Ac[Phe 1, 2, 3,Arg,D-Ala]Dy n A(1-11)NH) 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 [NMePhe 1]arodyn shows even higher affinity and selectivity for κ opioid receptors (Bennett et al., J Pept Res 2005, 65, 322). However, the latter compound is prone to deletion of the Ac-NMePhe moiety from the N-terminus of the peptide during acidic cleavage as described in the accompanying paper. Several stable analogs of [NMePhe 1]arodyn and [NMePhe 1,Trp 3]arodyn where the acetyl group was substituted with a heteroatom-containing group were evaluated for their opioid receptor affinity, selectivity, and efficacy. Methoxycarbonyl derivatives exhibited the highest κ opioid receptor affinity among the analogs. Additional [CHOCO-NMePhe 1]arodyn analogs where position 3 was substituted with other aromatic or nonaromatic residues were also evaluated for κ receptor affinity, selectivity, and efficacy. [CHOCO-NMePhe 1]arodyn has similar κ opioid receptor affinity as [NMePhe 1]arodyn, retains high κ opioid receptor selectivity, and is a potent κ opioid receptor antagonist.

Original languageEnglish (US)
Pages (from-to)103-110
Number of pages8
Issue number1
StatePublished - Jul 6 2011


All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Biomaterials
  • Organic Chemistry

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