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Cyclic enkephalin-deltorphin hybrids containing a carbonyl bridge: structure and opioid activity

Ciszewska, Małgorzata and Ruszczyńska, Katarzyna and Oleszczuk, Marta and Chung, Nga N. and Witkowska, Ewa and Schiller, Peter W. and Wójcik, Jacek and Izdebski, Jan (2011) Cyclic enkephalin-deltorphin hybrids containing a carbonyl bridge: structure and opioid activity. Acta Biochimica Polonica, 58 (2). pp. 225-230. ISSN PL ISSN 0001-527X

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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.

Item Type:Article
Subjects:Q Science > QD Chemistry
Divisions:Laboratory of Biological NMR
ID Code:107
Deposited By: dr hab. Jacek Wójcik
Deposited On:28 Jun 2011 08:55
Last Modified:15 Oct 2014 10:21

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