IJOC  Vol.2 No.1 , March 2012
Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives
Abstract: Endomorphin-1 is an endogenous opioid peptide that mediates pain relief through interaction with the μ-opioid receptor in the central nervous system. To enhance the metabolic stability of this tetrapeptide, cyclisation through the formation of a disulfide bridge between the side chains of cysteine residues added to the sequence was explored. A further increase in stability was achieved through N-terminal modification with lipoamino acid and lactose succinamic acid, and the inclusion of D-amino acids. The latter also provided an alternative spatial arrangement of the aromatic side chains. The lipidated cyclic derivatives were insoluble in aqueous buffer, however, the cyclic peptides and glycopeptides showed greatly improved stability towards enzymatic degradation in human plasma.
Cite this paper: F. M. Mansfeld and I. Toth, "Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives," International Journal of Organic Chemistry, Vol. 2 No. 1, 2012, pp. 1-6. doi: 10.4236/ijoc.2012.21001.

[1]   S. Morimoto, K. Suemori, J. Moriwaki, F. Taura, H. Tanaka, M. Aso, M. Tanaka, H. Suemune, Y. Shimohigashi and Y. Shoyama, “Morphine Metabolism in the Opium Poppy and Its Possible Physiological Function—Bio-chemical Characterization of the Morphine Metabolite, Bismorphine,” Journal of Biological Chemistry, Vol. 276, No. 41, 2001, pp. 38179-38184. doi:10.1074/jbc.M107105200

[2]   J. E. Zadina, L. Hackler, L. J. Ge and A. J. Kastin, “A Potent and Selective Endogenous agonist for the Mu-Opiate Receptor,” Nature, Vol. 386, No. 6624, 1997, pp. 499-502. doi:10.1038/386499a0

[3]   Y. Okada, A. Fukumizu, M. Takahashi, Y. Shimizu, Y. Tsuda, T. Yokoi, S. D. Bryant and L. H. Lazarus, “Synthesis of Stereoisomeric Analogues of Endomorphin-2, H-Tyr-Pro-Phe-Phe-NH2, and Examination of Their Opioid Receptor Binding Activities and Solution Confor- mation,” Biochemical and Biophysical Research Communications, Vol. 276, No. 1, 2000, pp. 7-11. doi:10.1006/bbrc.2000.3416

[4]   M. G. Paterlini, F. Avitabile, B. G. Ostrowski, D. M. Ferguson and P. S. Portoghese, “Ste-reochemical Require- ments for Receptor Recognition of the Mu-Opioid Peptide Endomorphin-1,” Biophysical Journal, Vol. 78, No. 2, 2000, pp. 590-599. doi:10.1016/S0006-3495(00)76619-7

[5]   J. Fichna, J. C. Do-Rego, P. Kosson, J. Costentin and A. Janecka, “Characteri-zation of Antinociceptive Activity of Novel Endomorphin-2 and Morphiceptin Analogs Modi- fied in the Third Position,” Biochemical Pharmacology, Vol. 69, No. 1, 2005, pp. 179-185. doi:10.1016/j.bcp.2004.09.011

[6]   G. Cardillo, L. Gentilucci, P. Melchiorre and S. Spampinato, “Synthesis and Binding Activity of Endomorphin-1 Analogues Containing Beta-Amino Acids,” Bioorganic & Medicinal Chemistry Letters, Vol. 10, No. 24, 2000, pp. 2755-2758. doi:10.1016/S0960-894X(00)00562-X

[7]   G. Cardillo, L. Gentilucci, A. R. Qasem, F. Sgarzi and S. Spampinato, “Endo-morphin-1 Analogues Containing Beta- Proline Are Mu-Opioid Receptor Agonists and Display Enhanced Enzymatic Hydrolysis Resistance,” Journal of Medicinal Chemistry, Vol. 45, No. 12, 2002, pp. 2571- 2578. doi:10.1021/jm011059z

[8]   S. Spampinato, A. R. Qasem, M. Calienni, G. Murari, L. Gentilucci, A. Tolomelli and G. Cardillo, “Antino- ciception by a Peripherally Administered Novel Endo- morphin-1 Analogue Containing Beta-Proline,” European Journal of Pharmacology, Vol. 469, No. 1-3, 2003, pp. 89-95. doi:10.1016/S0014-2999(03)01736-9

[9]   Y. Okada, Y. Fujita, T. Motoyama, Y. Tsuda, T. Yokoi, T. Y. Li, Y. Sasaki, A. Ambo, Y. Jinsmaa, S. D. Bryant and L. H. Lazarus, “Structural Studies of [2',6'-Dimethyl- L-tyrosine(1)]endomorphin-2 Analo-gues: Enhanced Activity and cis Orientation of the Dmt-Pro Amide Bond,” Bioor- ganic & Medicinal Chemistry, Vol. 11, No. 9, 2003, pp. 1983-1994. doi:10.1016/S0968-1896(03)00068-3

[10]   Y. Jinsmaa, E. Marczak, Y. Fujita, K. Shiotani, A. Miya- zaki, T. Y. Li, Y. Tsuda, A. Arnbo, Y. Sasaki, S. D. Bry- ant, Y. Okada and L. H. Lazarus, “Potent in Vivo Antino- ciception and Opioid Receptor Preference of the Novel Analogue [Dmt(1)]endomorphin-1,” Pharmacology, Biochemistry and Behavior, Vol. 84, No. 2, 2006, pp. 252- 258. doi:10.1016/j.pbb.2006.05.005

[11]   Y. Koda, M. Del Borgo, S. T. Wessling, L. H. Lazarus, Y. Okada, I. Toth and J. T. Blanchfield, “Synthesis and in Vitro Evaluation of a Library of Modified Endomorphin-1 Peptides,” Bioorganic & Medicinal Chemistry, Vol. 16, No. 11, 2008, pp. 6286-6296. doi:10.1016/j.bmc.2008.04.020

[12]   Y. Koda, M. T. Liang, J. T. Blanchfield and I. Toth, “In Vitro Stability and Permeability Studies of Liposomal Delivery Systems for a Novel Lipophilic Endomorphin-1 Analogue,” International Journal of Pharma-ceutics, Vol. 356, No. 1-2, 2008, pp. 37-43. doi:10.1016/j.ijpharm.2007.12.036

[13]   C. Adessi and C. Soto, “Converting a Peptide into a Drug: Strategies to Improve Stability and Bioavailability,” Current Medicinal Chemistry, Vol. 9, No. 9, 2002, pp. 963-978. doi:10.2174/0929867024606731

[14]   L. Gentilucci, R. De Marco and L. Cerisoli, “Chemical Modifications Designed to Improve Peptide Stability: Incorporation of Non-Natural Amino Acids, Pseudo-Peptide Bonds, and Cyclization,” Current Pharmaceutical Design, Vol. 16, No. 28, 2010, pp. 3185-3203. doi:10.2174/138161210793292555

[15]   G. Cardillo, L. Genti-lucci, A. Tolomelli, R. Spinosa, M. Calienni, A. R. Qasem and S. Spampinato, “Synthesis and Evaluation of the Affinity toward Mu-Opioid Receptors of Atypical, Lipophilic Ligands Based on the Sequence c[-Tyr-Pro-Trp-Phe-Gly-],” Journal of Medicinal Chemistry, Vol. 47, No. 21, 2004, pp. 5198-5203. doi:10.1021/jm0498811

[16]   L. Gentilucci, A. Tolomelli and F. Squassabia, “Topological Exploration of Cyclic Endomorphin-1 Analogues, Structurally Defined Models for Investigating the Bioactive Conformation of MOR Agonists,” Protein and Peptide Letters, Vol. 14, No. 1, 2007, pp. 51-56. doi:10.2174/092986607779117218

[17]   L. Gentilucci, F. Squassabia, R. Demarco, R. Artali, G. Cardillo, A. Tolomelli, S. Spampinato and A. Bedini, “Investigation of the Interaction between the Atypical Agonist c[YpwFG] and MOR,” FEBS Journal, Vol. 275, No. 9, 2008, pp. 2315-2337. doi:10.1111/j.1742-4658.2008.06386.x

[18]   A. Janecka, J. Fichna, R. Kruszynski, Y. Sasaki, A. Ambo, J. Costentin and J. C. do-Rego, “Synthesis and Antinociceptive Activity of Cyclic Endomorphin-2 and Morphiceptin Analogs,” Biochemical Pharmacology, Vol. 71, No. 1-2, 2005, pp. 188-195. doi:10.1016/j.bcp.2005.10.018

[19]   R. Perlikowska, J. C. do-Rego, A. Cravezic, J. Fichna, A. Wyrebska, G. Toth and A. Janecka, “Synthesis and Biological Evaluation of Cyclic En-domorphin-2 Analogs,” Peptides, Vol. 31, No. 2, 2010, pp. 339-345. doi:10.1016/j.peptides.2009.12.002

[20]   I. Toth, J. P. Malkin-son, N. S. Flinn, B. Drouillat, A. Horvath, J. Erchegyi, M. Idei, A. Venetianer, P. Artursson, L. Lazorova, B. Szende and G. Keri, “Novel Lipoamino Acid- and Liposaccharide-Based System for Peptide Delivery: Application for Oral Administration of Tumor-Selective Somatostatin Analogues,” Journal of Medicinal Chemistry, Vol. 42, No. 19, 1999, pp. 4010- 4013. doi:10.1021/jm9910167

[21]   P. Simerska, P. M. Moyle and I. Toth, “Modern Lipid-, Carbohydrate-, and Peptide-Based Deli-very Systems for Peptide, Vaccine, and Gene Products,” Medi-cinal Research Reviews, Vol. 31, No. 4, 2009, pp. 520-547. doi:10.1002/med.20191

[22]   R. Polt and M. M. Palian, “Gly-copeptide Analgesics,” Drugs of the Future, Vol. 26, No. 6, 2001, pp. 561-576. doi:10.1358/dof.2001.026.06.668342

[23]   J.-P. Meyer, N. Collins, F.-D. Lung, P. Davis, T. Zalewska, F. Porreca, H. I. Yamamura and V. J. Hruby, “Design, Synthesis, and Biological Properties of highly Potent Cyclic Dynorphin a Analogs. Ana-logs Cyclized between Positions 5 and 11,” Journal of Medicinal Chemistry, Vol. 37, No. 23, 1994, pp. 3910-3917. doi:10.1021/jm00049a010

[24]   H. I. Mosberg, R. Hurst, V. J. Hruby, K. Gee, H. I. Yamamura, J. J. Galligan and T. F. Burks, “Bis-Penicil- lamine Enkephalins Possess Highly Improved Specificity toward Delta Opioid Receptors,” Proceedings of the National Academy of Sciences USA, Vol. 80, No. 19, 1983, pp. 5871-5874. doi:10.1073/pnas.80.19.5871

[25]   P. W. Schiller, G. Weltrowska, T. M. D. Nguyen, C. Lemieux, N. N. Chung and Y. X. Lu, “Conversion of Delta-, Kappa- and Mu-Receptor Selective Opioid Peptide Agonists into Delta-, Kappa- and Mu-Selective Antagonists,” Life Sciences, Vol. 73, No. 6, 2003, pp. 691-698. doi:10.1016/S0024-3205(03)00389-8

[26]   W. Pan and A. J. Kastin, “From MIF-1 to Endomorphin: The Tyr-MIF-1 Family of Peptides,” Peptides, Vol. 28, No. 12, 2007, pp. 2411-2434. doi:10.1016/j.peptides.2007.10.006

[27]   R. Yamada and Y. Kera, “D-Amino Acid Hydrolysing Enzymes,” EXS, Vol. 85, 1998, pp. 145-155. doi:10.1007/978-3-0348-8837-0_9

[28]   R. Polt, F. Porreca, L. Z. Szabo, E. J. Bilsky, P. Davis, T. J. Abbruscato, T. P. Davis, R. Horvath, H. I. Yamamura and V. J. Hruby, “Glycopeptide Enkephalin Analogs Produce Analgesia in Mice—Evidence for Penetration of the Blood-Brain-Barrier,” Proceedings of the National Academy of Sciences of the USA, Vol. 91, No. 15, 1994, pp. 7114-7118. doi:10.1073/pnas.91.15.7114

[29]   S. Horvat, “Opioid Peptides and Their Glycoconjugates: Structure-Activity Relationships,” Current Medicinal Chemistry: Central Nervous System Agents, Vol. 1, No. 2, 2001, pp. 133-154. doi:10.2174/1568015013358581

[30]   N. O. Elmagbari, R. D. Egleton, M. M. Palian, J. J. Lowery, W. R. Schmid, P. Davis, E. Navratilova, M. Dhanasekaran, C. M. Keyari, H. I. Yamamura, F. Porreca, V. J. Hruby, R. Polt and E. J. Bilsky, “Antinociceptive Structure-Activity Studies with Enkepha-lin-Based Opioid Glycopeptides,” Journal of Pharmacology and Experimental Therapeutics, Vol. 311, No. 1, 2004, pp. 290-297. doi:10.1124/jpet.104.069393

[31]   W. A. Gibbons, R. A. Hughes, M. Charalambous, M. Christodoulou, A. Szeto, A. E. Aulabaugh, P. Mascagni and I. Toth, “Lipidic Peptides 1. Syn-thesis, Resolution and Structural Elucidation of Lipidic Ami-no-Acids and Their Homo-Oligomers and Heterooligomers,” Liebigs Annalen der Chemie, Vol., No. 12, 1990, pp. 1175-1183. doi:10.1002/jlac.1990199001215

[32]   P. Alewood, D. Ale-wood, L. Miranda, S. Love, W. Meutermans and D. Wilson, “Rapid in Situ Neutralization Protocols for Boc and Fmoc Solid-Phase Chemistries,” Methods in Enzymology, Vol. 289, 1997, pp. 14-29. doi:10.1016/S0076-6879(97)89041-6