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Cyclic Opioid Peptide Agonists and Antagonists Obtained Via Ring‐Closing Metathesis
Author(s) -
Berezowska Irena,
Lemieux Carole,
Chung Nga N.,
Wilkes Brian C.,
Schiller Peter W.
Publication year - 2009
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2009.00867.x
Subject(s) - ring closing metathesis , closing (real estate) , cyclic peptide , chemistry , stereochemistry , opioid , peptide , combinatorial chemistry , opioid peptide , metathesis , pharmacology , medicine , receptor , biochemistry , organic chemistry , business , finance , polymerization , polymer
The opioid peptide H‐Tyr‐c[D‐Cys‐Phe‐Phe‐Cys]NH 2 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 (2 S )‐2‐methyl‐3‐(2,6‐dimethyl‐4‐hydroxyphenyl)propanoic acid [(2 S )‐Mdp] in the 1‐position were prepared. The peptides were synthesized on solid‐phase by substituting d ‐allylglycine and (2 S )‐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 –CH 2 –CH 2 – bridged peptides. All six Tyr 1 ‐ and Dmt 1 ‐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 Dhp 1 ‐ and (2 S )‐Mdp 1 ‐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 Phe 3 and Phe 4 side chains.