title: Synthesis, Biological Activity, and NMR-Based Structural Studies of Deltorphin I Analogs Modified in Message Domain with a New α,α-Disubstituted Glycines.
abstract: This article describes new deltorphin I analogs in which phenylalanine residues were replaced by the corresponding (R) or (S)-α-benzyl-β-azidoalanine, α-benzyl-β-(1-pyrrolidinyl)alanine, α-benzyl-β-(1-piperidinyl)alanine, and α-benzyl-β-(4-morpholinyl)-alanine residues. The potency and selectivity of the new analogs were evaluated by a competitive receptor binding assay in the rat brain using [(3) H]DAMGO (a μ ligand) and [(3) H]DELT (a δ ligand). The affinity of analogs containing (R) or (S)-α-benzyl-β-azidoalanine in position 3 to δ-receptors strongly depended on the chirality of the α,α-disubstituted residue. The conformational behavior of peptides modified with (R) or (S)-α-benzyl-β-(1-piperidinyl)Ala, which displays the opposite selectivity, was analyzed by (1) H and (13) C NMR. The μ-selective Tyr-d-Ala-(R)-α-benzyl-β-(1-piperidinyl)Ala-Asp-Val-Val-Gly-NH2 lacks the helical conformation observed in the δ-selective Tyr-d-Ala-(S)-α-benzyl-β-(1-piperidinyl)Ala-Asp-Val-Val-Gly-NH2 . Our results support the proposal that differences between δ- and μ-selective opioid peptides are attributable to the presence or absence of a spatial overlap between the N-terminal message domain and the C-terminal address domain.
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: Adriana
authors.initials: A
authors.lastname: Muchowska
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: 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 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: D000818:Animals; D005998:Glycine / Q000737:chemistry* / Q000235:genetics; D009842:Oligopeptides / Q000737:chemistry* / Q000235:genetics; D017433:Protein Structure, Secondary; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; C060208:deltorphin I, Ala(2)-; D005998:Glycine
keywords: NMR-based studies; deltorphin I analogues; opioid activities; α,α-disubstituted glycines