Cyclic Opioid Peptide Agonists and Antagonists Obtained Via Ring‐Closing Metathesis |
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Authors: | Irena Berezowska Carole Lemieux Nga N Chung Brian C Wilkes Peter W Schiller |
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Institution: | 1. 1Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC, Canada H2W 1R7;2. 2Department of Pharmacology, Université de Montréal, Montreal, QC, Canada ‐ H3C 3JT |
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Abstract: | The opioid peptide H‐Tyr‐cD‐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. |
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Keywords: | opioid activity profiles opioid peptide analogues opioid peptide SAR peptide synthesis ring‐closing metathesis |
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