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

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.