Deletion of Ac-NMePhe1from [NMePhe1]arodyn under acidic conditions, part 2: Effects of substitutions on pharmacological activity

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 ? opioid receptor antagonist (Bennett et al., J Med Chem 2002, 45, 5617), and its analog [NMePhe1]arodyn shows even higher affinity and selectivity for ? 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 [NMePhe1]arodyn and [NMePhe1,Trp3]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 ? opioid receptor affinity among the analogs. Additional [CH3OCO-NMePhe1]arodyn analogs where position 3 was substituted with other aromatic or nonaromatic residues were also evaluated for ? receptor affinity, selectivity, and efficacy. [CH3OCO-NMePhe1]arodyn has similar ? opioid receptor affinity as [NMePhe1]arodyn, retains high ? opioid receptor selectivity, and is a potent ? opioid receptor antagonist. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 103–110, 2011.