Preferences help
enabled [disable] Abstract
Number of results
2011 | 58 | 2 | 225-230
Article title

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

Title variants
Languages of publication
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.
Physical description
  • Peptide Laboratory, Department of Chemistry, University of Warsaw, Warszawa, Poland
  • Laboratory of Biological NMR, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, Poland
  • Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
  • Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, Quebec H2W IR7, Canada
  • Peptide Laboratory, Department of Chemistry, University of Warsaw, Warszawa, Poland
  • Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, Quebec H2W IR7, Canada
  • Laboratory of Biological NMR, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, Poland
  • Peptide Laboratory, Department of Chemistry, University of Warsaw, Warszawa, Poland
  • Akiyama K, Gee KW, Mosberg HI, Hruby VJ, Yamamura HI (1985) Characterization of [3H][2-D-penicillamine, 5-d-penocillamine]-enkephalin binding to δ opiate receptors in the rat brain and neuroblastoma-glioma hybrid cell line (NG 108-15). Proc Natl Acad Sci USA 82: 2543-2547.
  • Aue WP, Bartholdi E, Ernst RR (1976) Two-dimensional spectroscopy. Application to nuclear magnetic resonance. J Chem Phys 64: 2229-2246.
  • Bax A, Davis DG (1985) Practical aspects of two-dimensional transverse NOE spectroscopy. J Magn Reson 63: 207-213.
  • Bax A, Freeman R (1985) Enhanced NMR resolution by restricting the effective sample volume. J Magn Reson 65: 355-360.
  • Bothner-By AA, Stephens RL, Lee J-M, Warren CD, Jeanloz RW (1984) Structure determination of tetrasaccharide: transient nuclear Overhauser effects in the rotating frame. J Am Chem Soc 106: 811-813.
  • Braunschweiler L, Ernst RR (1983) Coherence transfer by isotropic mixing: application to proton correlation spectroscopy. J Magn Reson 53: 521-528.
  • Charpentier S, Sagan S, Delfour A, Nicolas P (1991) Dermenkephalin and deltorphin I reveal similarities within ligand-binding domains of μ- and δ-opioid receptors and an additional address subside on the δ-receptor. Biochem Biophys Res Commun 179: 1161-1168.
  • Cheng PY, Wu D, Soong Y, McCabe S, Decena JA, Szeto HH (1993) Role of mu 1- and delta-opioid receptors in modulation of fetal EEG and respiratory activity. Am J Physiol 265: R433-438.
  • Ciszewska M, Kwasiborska M, Nowakowski M, Oleszczuk M, Wójcik J, Chung NN, Schiller PW, Izdebski J (2009) N-(ureidoethyl)amides of cyclic enkephalin analogs. J Pept Sci 15: 312-318.
  • Cohen JH, Abdel-Magid AF, Almond Jr HR, Maryanoff CA (2002) Stereoselective synthesis of beta-aryl-beta-amino esters. Tetrahedron Lett 43: 1977-1981.
  • Cowan A, Zhu XZ, Mosberg HI, Omnaas JR, Porrwca F (1988) Direct dependence studies in rats with agents selective for different types of opioid receptor. J Pharmacol Exp Ther 246: 950-955.
  • Davies J (2003) The cyclization of peptides and depsipeptides. J Pept Sci 9: 471-501.
  • DiMaio J, Schiller PW (1980) A cyclic enkephalin analog with high in vitro opiate activity. Proc Natl Acad Sci USA 77: 7162-7166.
  • Filip K, Oleszczuk M, Pawlak D, Wójcik J, Chung NN, Schiller PW, Izdebski J (2003) Potent side-chain to side-chain cyclized dermorphin analogues containing a carbonyl bridge. J Pept Sci 9: 649-657.
  • Filip K, Oleszczuk M, Wójcik J, Chung NN, Schiller PW, Pawlak D, Zieleniak A, Parcińska A, Witkowska E, Izdebski J (2005) Cyclic enkephalin and dermorphin analogues containing a carbonyl bridge. J Pept Sci 11: 347-352.
  • Gutkowska J, Jankowski M, Pawlak D, Makaddam-Daher S, Izdebski J (2004) The cardiovascular and renal effects of highly potent μ-opioid receptor agonist, cyclo[Nε,Nβ-carbonyl-d-Lys2, Dap5]enkephalinamide. Eur J Pharmacol 496: 167-174.
  • Hendrson G, Hughes J, Kosterlitz H (1972) A new example of morphine sensitive neuroeffector junction. Br J Pharmacol 46: 764-766.
  • Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14: 33-38.
  • Janecka A, Kruszynski R (2005) Conformationally restricted peptides as tools in opioid receptor studies. Curr Med Chem 12: 471-481.
  • Kay LE, Keifer P, Saarinen T (1992) Pure absorption gradient-enhanced heteronuclear single quantum correlation spectroscopy with improved sensitivity. J Am Chem Soc 114: 10663-10665.
  • Kotlińska J, Bochenski M, Lagowska-Lenard M, Gibula-Bruzda E, Witkowska E, Izdebski J (2009) Enkephalin derivative, cyclo[Nε,Nβ -carbonyl-d-Lys2, Dap5]enkephalinamide (CUENK6), induces a highly potent antinociception in rats. Neuropeptides 43: 221-228.
  • Li Z, Scheraga HA (1987) Monte Carlo-minimization approach to the multiple-minima problem in protein folding. Proc Natl Acad Sci USA 84: 6611-6615.
  • Liwo A, Tempczyk A, Oldziej S, Shenderowicz MD, Hruby VJ, Talluri S, Ciarkowski J, Kasprzykowski F, Lankiewicz L, Grzonka Z (1996) Exploration of the conformational space of oxytocin and arginine-vasopressin using the electrostatically driven Monte Carlo and Molecular Dynamics methods. Biopolymers 38: 157-175.
  • Marquardt DW (1963) An algorithm for least-squares estimation of nonlinear parameters. J Soc Indust Appl Math 11: 431-441.
  • Masman MF, Rodriguez AM, Svetaz L, Zacchino SA, Somlai C, Csizmadia IG, Penke B, Enriza RD (2006) Synthesis and conformational analysis of His-Phe-Arg-Trp-NH2 and analogues with antifungal properties. Bioorg Med Chem 14: 7604-7614.
  • Masman MP, Somlai C, Garibotto FM, Rodriguez AM, de la Iglesia A, Zacchino SA, Penke B, Enriza RD (2008) Structure-antifungal activity relationship of His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 and analogues. Bioorg Med Chem 16: 4347-4358.
  • Meadows RP, Post CB, Luxon BA, Gorenstein DG (1994) MORASS 2.1. W. Lafayette Pardue University.
  • Misicka A, Lipkowski A, Horvath R, Davis P, Porreca F, Yamamura HI, Hruby VJ. (1994) Delta opioid receptor selective ligands; DPLPE-deltorphin chimeric peptide analogues. Int J Pept Protein Res 44: 80-84.
  • Nemethy G, Gibson KD, Palmer KA, Yoon CN, Paterlini G, Zagari A, Rumsey S, Sheraga HA (1992) Energy parameters in polypeptides. 10. Improved geometrical parameters and nonbonded interactions for use in the ECEPP/3 algoritm, with application to praline-containing peptides. J Phys Chem 96: 6472-6484.
  • Palmer III AG, Cavanagh J, Wright PE, Rance M (1991) Sensitivity improvement in proton detected heteronuclear correlation experiments. J Magn Reson 93: 151-170.
  • Paton WDM (1957) The action of morphine and related substances on contraction on acylcholine output of coaxially stimulated guinea pig ileum. Br J Pharmacol 12: 119-127.
  • Pawlak D, Chung NN, Schiller PW, Izdebski J (1997) Synthesis of a novel side-chain to side-chain cyclized enkephalin analogues containing a carbonyl bridge. J Pept Sci 3: 277-281.
  • Pawlak D, Oleszczuk M, Wójcik J, Pachulska M, Chung NN, Schiller PW, Izdebski J (2001) Highly potent side-chain to side-chain cyclized enkephalin analogs containing a carbonyl bridge: synthesis, biology and conformation. J Pept Sci 7: 128-140.
  • Su YF, McNutt RW, Chung KJ (1998) Delta-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception. J Pharmacol Exp Ther 287: 815-823.
  • Schiller PW, Lipton A, Horrobin DF, Bodanszky M (1978) Unsulfated C-terminal 7-peptide of cholecystokinin: a new ligant of the opiate receptor. Biochem Biophys Res Commun 85: 1332-1338.
  • Sidor M, Wójcik J, Pawlak D, Izdebski J (1999) Conformational analysis of a novel cyclic enkephalin analogue using NMR and EDMC calculations. Acta Biochim Pol 46: 641-650.
  • Spath H (1980) Cluster Analysis Algorithms. Halsted Press, New York.
  • Vila J, Wiliams RI, Vasquez M, Scheraga HA (1991) Empirical solvation models can be used to differentiate native from near-native conformations of bovine pancreatic trypsin inhibitor. Proteins: Struct Funct Genet 10: 199-218.
  • Waterfield AA, Leslie FM, Lord JAH, Ling N (1979) Opioid activities of fragments of β-endorphin and of its leucine65-analogue 5. Eur J Pharmacol 58: 11-18.
  • Wishart DS, Bigam CG, Yao J, Abildgaard F, Dyson HJ, Oldfield E, Markley JL, Sykes BDl (1995) 1H, 13C, 15N chemical shift referencing in biomolecular NMR. J Biomol NMR 6: 135-140.
  • Wiszniewska A, Kunce D, Chung NN, Schiller PW, Izdebski J (2005) p-Nitrophenoxycarbonyl derivatives of Boc-protected diaminoalkanes in the synthesis of enkephalin peptidomimetics. J Pept Sci 11: 579-583.
  • in Press
  • Zieleniak A, Rodziewicz-Motowidło S, Rusak Ł, Chumg NN, Czaplewski C, Witkowska E, Schiller PW, Ciarkowski J, Izdebski J (2008) Deltorphin analogs restricted via a urea structure and opioid activity. J Pept Sci 14: 830-837.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.