The impact of β-azido(or 1-piperidinyl)methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues
| Autor: | Andrzej Ejchart, Anika Lasota, Aleksandra Misicka, Oliwia Frączak, Maciej Maciejczyk, Aleksandra Olma, Piotr Kosson, Michał Nowakowski |
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| Rok vydání: | 2016 |
| Předmět: |
Pharmacology
chemistry.chemical_classification Alanine 010405 organic chemistry Chemistry Stereochemistry Organic Chemistry Absolute configuration Peptide Phenylalanine General Medicine Dermorphin 010402 general chemistry Ligand (biochemistry) 01 natural sciences Biochemistry 0104 chemical sciences chemistry.chemical_compound Structural Biology Drug Discovery Molecular Medicine Structure–activity relationship Epimer Molecular Biology |
| Zdroj: | Journal of Peptide Science. 22:545-551 |
| ISSN: | 1075-2617 |
| DOI: | 10.1002/psc.2903 |
| Popis: | The synthesis of new dermorphin analogues is described. The (R)-alanine or phenylalanine residues of natural dermorphin were substituted by the corresponding α-methyl-β-azidoalanine or α-benzyl-β-azido(1-piperidinyl)alanine residues. The potency and selectivity of the new analogues were evaluated by a competitive receptor binding assay in rat brain using [(3) H]DAMGO (a μ ligand) and [(3) H]DELT (a δ ligand). The most active analogue in this series, Tyr-(R)-Ala-(R)-α-benzyl-β-azidoAla-Gly-Tyr-Pro-Ser-NH2 and its epimer were analysed by (1) H and (13) C NMR spectroscopy and restrained molecular dynamics simulations. The dominant conformation of the investigated peptides depended on the absolute configuration around C(α) in the α-benzyl-β-azidoAla residue in position 3. The (R) configuration led to the formation of a type I β-turn, whilst switching to the (S) configuration gave rise to an inverse β-turn of type I', followed by the formation of a very short β-sheet. The selectivity of Tyr-(R)-Ala-(R) and (S)-α-benzyl-β-azidoAla-Gly-Tyr-Pro-Ser-NH2 was shown to be very similar; nevertheless, the two analogues exhibited different conformational preferences. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. |
| Databáze: | OpenAIRE |
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