The impact of β‐azido(or 1‐piperidinyl)methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues |
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Authors: | Oliwia Frączak Piotr Kosson Aleksandra Misicka Michał Nowakowski Andrzej Ejchart Aleksandra Olma |
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Affiliation: | 1. Institute of Organic Chemistry, Lodz University of Technology, Lodz, Poland;2. Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland;3. Faculty of Chemistry, University of Warsaw, Warsaw, Poland;4. Centre of New Technologies, University of Warsaw, Warsaw, Poland;5. Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland |
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Abstract: | 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 [3H]DAMGO (a μ ligand) and [3H]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 1H and 13C NMR spectroscopy and restrained molecular dynamics simulations. The dominant conformation of the investigated peptides depended on the absolute configuration around Cα 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. |
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Keywords: | dermorphin analogues α ,α ‐disubstituted glycines CSPPS binding affinity to δ ‐ and μ ‐opioid receptors conformational analysis |
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