Exploring the Backbone of Enkephalins To Adjust Their Pharmacological Profile for the δ-Opioid Receptor
| Autor: | Véronique Bournival, Yves L. Dory, Louis Gendron, Arnaud Proteau-Gagné, Kristina Rochon |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Physiology medicine.drug_class Stereochemistry Cognitive Neuroscience Enkephalin Methionine Molecular Conformation Peptide Biochemistry Binding Competitive Cell Line δ-opioid receptor chemistry.chemical_compound Mice Structure-Activity Relationship Opioid receptor Receptors Opioid delta medicine Structure–activity relationship Peptide bond Animals chemistry.chemical_classification Dipeptide Ligand binding assay Biological activity Cell Biology General Medicine Enkephalins chemistry Indicators and Reagents Mitogen-Activated Protein Kinases Enkephalin Leucine Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|