title: The impact of β-azido(or 1-piperidinyl)methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues.
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.
authors.affiliation: Department of Physics and Biophysics, Faculty of Food Science, University of Warmia and Mazury, Oczapowskiego 4, 10-719, Olsztyn, Poland.|Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, ul. Ks. Trojdena 4, 02-109, Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Maciejczyk
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924, Lodz, Poland.
authors.forename: Anika
authors.initials: A
authors.lastname: Lasota
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924, Lodz, Poland.
authors.forename: Oliwia
authors.initials: O
authors.lastname: Frączak
authors.affiliation: Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 01-793, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kosson
authors.affiliation: Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 01-793, Warsaw, Poland.|Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093, Warsaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Misicka
authors.affiliation: Centre of New Technologies, University of Warsaw, Banacha 2C, 02-097, Warsaw, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Nowakowski
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5A, 02-106, Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Ejchart
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924, Lodz, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Olma
mesh_terms: D000409:Alanine / Q000737:chemistry; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000737:chemistry; D001665:Binding Sites; D001667:Binding, Competitive; D001923:Brain Chemistry; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D008024:Ligands; D056004:Molecular Dynamics Simulation; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010649:Phenylalanine / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D001386:Azides; D008024:Ligands; D018847:Opioid Peptides; D010880:Piperidines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C030058:dermorphin; D010649:Phenylalanine; D000409:Alanine
keywords: CSPPS; binding affinity to δ- and μ-opioid receptors; conformational analysis; dermorphin analogues; α,α-disubstituted glycines