title: Deltorphin analogs restricted via a urea bridge: structure and opioid activity.
abstract: Eight cyclic heptapeptides related to the full sequence of deltorphin have been synthesized. The synthesis of linear peptides containing diamino acid residues in positions 2 and 4 was carried out on a 4-methylbenzhydrylamine resin. Depending on protection procedures, the N-protected peptide-resins or N-protected peptide amides with free amino groups in the side chains were obtained, which were subsequently treated with bis-(4-nitrophenyl)carbonate to form a urea unit. Opioid activities of the peptides were determined in the guinea pig ileum (GPI) and mouse vas deferens (MVD) assays. Several compounds showed high delta opioid agonist potency and high selectivity for delta receptors. The results were compared with those obtained earlier for respective 1-4 deltorphin analogs. The conformations of these peptides have been studied using 2D-NMR in H2O/D2O and molecular dynamics. We observed that the backbone rings had well defined conformations, while the Tyr and Phe side chains and the C-terminal tail had significant conformational freedom. The bioassay data and conformational parameters of these peptides were compared with those of previously described, corresponding 1-4 deltorphin analogs. This comparison permitted an assessment of the role of the C-terminal peptide segment in defining the conformation and receptor interaction of the N-terminal portion and provided insight into the relationship between the putative bioactive conformations and bioactivity.
authors.affiliation: Peptide Laboratory, Department of Chemistry, Warsaw University, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zieleniak
authors.forename: Sylwia
authors.initials: S
authors.lastname: Rodziewicz-Motowidło
authors.forename: Lukasz
authors.initials: L
authors.lastname: Rusak
authors.forename: Nga N
authors.initials: NN
authors.lastname: Chung
authors.forename: Cezary
authors.initials: C
authors.lastname: Czaplewski
authors.forename: Ewa
authors.initials: E
authors.lastname: Witkowska
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.forename: Jerzy
authors.initials: J
authors.lastname: Ciarkowski
authors.forename: Jan
authors.initials: J
authors.lastname: Izdebski
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D003198:Computer Simulation; D007082:Ileum / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine; D014508:Urea / Q000737:chemistry*
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; C059567:deltorphin; D014508:Urea