Conversion of δ-, κ- and μ-receptor selective opioid peptide agonists into δ-, κ- and μ-selective antagonists

Abstract

2′,6′-Dimethyl substitution of the Tyr1 residue of opioid agonist peptides and deletion of the positively charged N-terminal amino group or its replacement with a methyl group has recently been shown to represent a general structural modification to convert opioid peptide agonists into antagonists. This conversion requires the syntheses of opioid peptide analogues containing either 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp] in place of Tyr1. Using this approach, δ-, κ- and μ-selective opioid peptide agonist peptides were successfully converted into corresponding δ-, κ- and μ-selective antagonists, whereby receptor selectivity was often maintained or even improved. Thus, two (2S)-Mdp1-analogues of the δ-selective cyclic enkephalin analogue H-Tyr-c[D-Pen-Gly-Phe(pF)-Pen]-Phe-OH turned out to be potent and selective δ antagonists. Most successful was the development of κ antagonists derived from dynorphin A (Dyn A), including the highly potent and selective κ-antagonist [(2S)-Mdp1]Dyn A(1-11)-NH2 (dynantin) and the enzymatically stable octapeptide analogue [(2S)-Mdp1,MeArg7,D-Leu8]Dyn A(1-8)-NH2. The (2S)-Mdp1-analogues of dynorphin B and α-neoendorphin also were κ antagonists and may be useful as pharmacological tools in studies of κ receptor subtypes. Finally, the Dhp1-analogues of the μ-selective cyclic enkephalin analogue H-Tyr-c[Nε,Nβ-carbonyl-D-Lys2,Dap5]enkephalinamide and of endomorphin-2 were moderately potent μ opioid antagonists.