Systematic replacement of amides by 1,4-disubstituted[1,2,3]triazoles in Leu-enkephalin and the impact on the delta opioid receptor activity

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 19; pp. 5267 - 5269
• Main Authors: Proteau-Gagné, Arnaud, Rochon, Kristina, Roy, Mélissa, Albert, Pierre-Julien, Guérin, Brigitte, Gendron, Louis, Dory, Yves L.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.10.2013; Elsevier
• Subjects: 1,2,3 Triazole; Amides - chemistry; Binding, Competitive; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Click chemistry; Contractility; Delta opioid receptor; Enkephalin, Leucine - chemistry; Enkephalin, Leucine - pharmacology; Hydrogen Bonding; Inhibitory Concentration 50; Leu-enkephalin; Life Sciences & Biomedicine; Molecular Structure; Peptidomimetics; Pharmacology & Pharmacy; Physical Sciences; Receptors, Opioid, delta - chemistry; Receptors, Opioid, delta - drug effects; Science & Technology; Triazoles - chemistry; 1,2,3 Triazole; Click chemistry; Delta opioid receptor; Leu-enkephalin; Peptidomimetics; DESIGN; ANALOGS; MIMICS; LIGATION; PEPTIDE; NEUROPATHIC PAIN; CYCLOADDITION; BACKBONE; AGONIST
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.08.020

[Display omitted] Using Cu(I)-catalyzed azide–alkyne cycloaddition in a mixed classical organic phase and solid phase peptide synthesis approach, we synthesized four analogs of Leu-enkephalin to systematically replace amides by 1,4-disubstituted[1,2,3]triazoles. The peptidomimetics obtained were characterized by competitive binding, contractility assays and ERK1/2 phosphorylation. The present study reveals that the analog bearing a triazole between Phe and Leu retains some potency, more than all the others, suggesting that the hydrogen bond acceptor capacity of the last amide of Leu-enkephalin is essential for the biological activity of the peptide.