Exploring the Backbone of Enkephalins To Adjust Their Pharmacological Profile for the δ-Opioid Receptor.
The role of each of the four amide bonds in Leu(5)-enkephalin was investigated by systematically and sequentially replacing each with its corresponding trans-alkene. Six Leu(5)-enkephalin analogs based on six dipeptide surrogates and two Met(5)-enkephalin analogs were synthesized and thoroughly tested using a δ-opioid receptor internalization assay, an ERK1/2 activation assay, and a competition binding assay to evaluate their biological properties. We observed that an E-alkene can efficiently replace the first amide bond of Leu(5)- and Met(5)-enkephalin without significantly affecting biological activity. By contrast, the second amide bond was found to be highly sensitive to the same modification, suggesting that it is involved in biologically essential intra- or intermolecular interactions. Finally, we observed that the affinity and activity of analogs containing an E-alkene at either the third or fourth position were partially reduced, indicating that these amide bonds are less important for these intra- or intermolecular interactions. Overall, our study demonstrates that the systematic and sequential replacement of amide bonds by E-alkene represents an efficient way to explore peptide backbones.
Laboratoire de Synthése Supramoléculaire, Départment de Chimie, Institut de Pharmacologie, Université de Sherbrooke, 3001, 12E Avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
Arnaud
A
Proteau-Gagné
Véronique
V
Bournival
Kristina
K
Rochon
Yves L
YL
Dory
Louis
L
Gendron
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D004745:Enkephalins / Q000737:chemistry* / Q000494:pharmacology*; D007202:Indicators and Reagents; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
D004745:Enkephalins; D007202:Indicators and Reagents; D017465:Receptors, Opioid, delta; D004744:Enkephalin, Methionine; D004743:Enkephalin, Leucine; D020928:Mitogen-Activated Protein Kinases