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Deletion of Ac‐NMePhe 1 from [NMePhe 1 ]arodyn under acidic conditions, part 2: Effects of substitutions on pharmacological activity
Author(s) -
Fang WeiJie,
Bennett Marco A.,
Murray Thomas F.,
Aldrich Jane V.
Publication year - 2011
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.21495
Subject(s) - chemistry , selectivity , stereochemistry , dynorphin , receptor , opioid receptor , moiety , heteroatom , dynorphin a , antagonist , opioid , μ opioid receptor , opioid peptide , peptide , biochemistry , organic chemistry , ring (chemistry) , catalysis
Arodyn (Ac[Phe 1,2,3 ,Arg 4 ,D‐Ala 8 ]Dyn A(1–11)NH 2 ) 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 [CH 3 OCO‐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. [CH 3 OCO‐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. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 103–110, 2011.