title: Cyclic enkephalin-deltorphin hybrids containing a carbonyl bridge: structure and opioid activity.
abstract: Six hybrid N-ureidoethylamides of octapeptides in which an N-terminal cyclic structure related to enkephalin was elongated by a C-terminal fragment of deltorphin were synthesized on MBHA resin. The synthetic procedure involved deprotection of Boc groups with HCl/dioxane and cleavage of the peptide resin with 45 % TFA in DCM. d-Lys and d-Orn were incorporated in position 2, and Lys, Orn, Dab, or Dap in position 5. The side chains of the dibasic amino function were protected with the Fmoc group. This protection was removed by treatment with 55 % piperidine in DMF, and cyclization was achieved by treatment with bis-(4-nitrophenyl)carbonate. Using various combinations of dibasic amino acids, peptides containing a 17-, 18-, 19- or 20-membered ring structure were obtained. The peptides were tested in the guinea-pig ileum (GPI) and mouse vas deferens (MVD) assays. Diverse opioid activities were observed, depending on the size of the ring. Extension of the enkephalin sequence at the C-terminus by a deltorphin fragment resulted in a change of receptor selectivity in favor of the δ receptor. The conformational propensities of selected peptides were determined using the EDMC method in conjunction with data derived from NMR experiments carried out in water. This approach allowed proper examination of the dynamical behavior of these small peptides. The results were compared with those obtained earlier with corresponding N-(ureidoethyl)pentapeptide amides.
authors.affiliation: Peptide Laboratory, Department of Chemistry, University of Warsaw, Warszawa, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Ciszewska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Ruszczyńska
authors.forename: Marta
authors.initials: M
authors.lastname: Oleszczuk
authors.forename: Nga N
authors.initials: NN
authors.lastname: Chung
authors.forename: Ewa
authors.initials: E
authors.lastname: Witkowska
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.forename: Jacek
authors.initials: J
authors.lastname: Wójcik
authors.forename: Jan
authors.initials: J
authors.lastname: Izdebski
mesh_terms: D000818:Animals; D004745:Enkephalins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D004745:Enkephalins; D009842:Oligopeptides; D010456:Peptides, Cyclic; C059567:deltorphin