The impact of β‐azido(or 1‐piperidinyl)methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues. (August 2016)

• Record Type: Journal Article
• Authors: Maciejczyk, Maciej; Lasota, Anika; Frączak, Oliwia; Kosson, Piotr; Misicka, Aleksandra; Nowakowski, Michał; Ejchart, Andrzej; Olma, Aleksandra
• Is Part Of: Journal of peptide science. Volume 22:Number 8(2016:Aug.)
• Page Start: 545
• Page End: 551
• Publication Date: 2016-08
• Subjects: dermorphin analogues -- α, α‐disubstituted glycines -- CSPPS -- binding affinity to δ‐ and μ‐opioid receptors -- conformational analysis; Peptides -- Periodicals; Peptides -- Periodicals; 572.65
• DOI: 10.1002/psc.2903
• Languages: English
• ISSNs: 1075-2617

Abstract

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 [ 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. Abstract : The synthesis and the potency and selectivity of new dermorphin analogues is described. The most active analogue in this series, Tyr‐( R )‐Ala‐( R )‐α‐benzyl‐β‐azidoAla‐Gly‐Tyr‐Pro‐Ser‐NH2 and its epimer were analyzed by 1 H and 13 C NMR spectroscopy and restrained MD simulations.