Cyclic Opioid Peptide Agonists and Antagonists Obtained Via Ring-Closing Metathesis

摘要

The opioid peptide H-Tyr-c[D-Cys-Phe-Phe-Cys]NH2 cyclized via a methylene dithiother is a potent and selective μ opioid agonist (Przydial M.J. et al., J Peptide Res, 66, 2005, 255). Dicarba analogues of this peptide with Tyr, 2′,6′-dimethyltyrosine (Dmt), 3-[2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp] in the 1-position were prepared. The peptides were synthesized on solid-phase by substituting d-allylglycine and (2S)-2-amino-5-hexenoic acid in position 2 and 5, respectively, followed by ring-closing metathesis. Mixtures of cis and trans isomers of the resulting olefinic peptides were obtained, and catalytic hydrogenation yielded the saturated –CH2–CH2– bridged peptides. All six Tyr¹- and Dmt¹-dicarba analogues retained high μ and δ opioid agonist potency and showed only slight or no preference for μ over δ receptors. As expected, the six Dhp¹- and (2S)-Mdp¹-dicarba analogues turned out to be μ opioid antagonists but, surprisingly, displayed a range of different efficacies (agonism, partial agonism or antagonism) at the δ receptor. The obtained results indicate that the μ versus δ receptor selectivity and the efficacy at the δ receptor of these cyclic peptides depend on distinct conformational characteristics of the 15-membered peptide ring structure, which may affect the spatial positioning of the exocyclic residue and of the Phe³ and Phe⁴ side chains.