Antagonism in opioid peptides: The role of conformation

Current Topics in Medicinal Chemistry

Volumn 4, Issue 1, 2004, Pages 147-157

  Salvadori, Severo ^a   Temussi, Piero A ^b,c,d  

^a UNIVERSITY OF FERRARA   (Italy)

^b UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^c NATIONAL INSTITUTE FOR MEDICAL RESEARCH   (United Kingdom)

^d ACCADEMIA NAZIONALE DEI LINCEI   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ADAMANTANE; BETA CASOMORPHINE DERIVATIVE; BINALTORPHIMINE; DELTA OPIATE RECEPTOR; DELTA OPIATE RECEPTOR AGONIST; DELTA OPIATE RECEPTOR ANTAGONIST; DERMORPHIN DERIVATIVE; DYNORPHIN A; DYNORPHIN[1-13]; DYNORPHIN[1-8]; ENKEPHALIN DERIVATIVE; ENKEPHALIN[2 DEXTRO PENICILLAMINE 5 PENICILLAMINE]; KAPPA OPIATE RECEPTOR; KAPPA OPIATE RECEPTOR ANTAGONIST; LEUCINE ENKEPHALIN DERIVATIVE; MORPHINE; MU OPIATE RECEPTOR; MU OPIATE RECEPTOR AGONIST; MU OPIATE RECEPTOR ANTAGONIST; N,N DIALLYLTYROSYL 2 METHYLALANYL 2 METHYLALANYLPHENYLALANYLLEUCINE; NALORPHINE; NALOXONE; NALTRINDOLE; NOCICEPTIN RECEPTOR ANTAGONIST; NORBINALTORPHIMINE; OCTREOTIDE; OPIATE ANTAGONIST; OPIATE PEPTIDE; SOMATOSTATIN DERIVATIVE; UNINDEXED DRUG; 7 SPIROINDANYLOXYMORPHONE; 7-SPIROINDANYLOXYMORPHONE; CYCLOPEPTIDE; DRUG DERIVATIVE; LEUCINE ENKEPHALIN; MORPHINE DERIVATIVE; OPIATE RECEPTOR; OXYMORPHONE; SPIRO COMPOUND;

BINDING AFFINITY; CHIRALITY; DRUG CONFORMATION; DRUG DESIGN; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG SPECIFICITY; HUMAN; NONHUMAN; PROTEIN CONFORMATION; PROTEIN DOMAIN; RETROSPECTIVE STUDY; REVIEW; THEORETICAL MODEL; ANIMAL; BINDING SITE; CHEMISTRY; DRUG ANTAGONISM; METABOLISM; PROTEIN TERTIARY STRUCTURE; STRUCTURE ACTIVITY RELATION;

ANIMALS; BINDING SITES; DRUG DESIGN; ENKEPHALIN, LEUCINE; HUMANS; MORPHINE DERIVATIVES; OPIOID PEPTIDES; OXYMORPHONE; PEPTIDES, CYCLIC; PROTEIN CONFORMATION; PROTEIN STRUCTURE, TERTIARY; RECEPTORS, OPIOID; RECEPTORS, OPIOID, DELTA; SPIRO COMPOUNDS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 2142661515     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/1568026043451564     Document Type: Review

References (86)

1. Morley, J. S. The design of antagonists of regulatory peptides and comments on their specificity. In Progress in Brain Research. Emson, P. C.; Rossor, M. N.; Tohyama, M. Eds.; Elsevier Science Publ. B. V. 1986, vol. 66, pp.333-340.
2. Rudinger, J.; Pliska, V.; Krejci, I. Oxytocin analogs in the analysis of some phases of hormone action. Recent Progr. Horm. Res. 1972, 28, 131-172.
3. Schwyzer, R. Estimated conformation, orientation, and accumulation of dynorphin A (1-13)-tridecapeptide on the surface of neutral lipid membranes. Biochemistry 1986, 25, 6335-6342.
4. Portoghese, P. S.; Sultana, M.; Nagase H.; Takemori A. E. Application of the message-address concept in the design of highly potent and selective non-peptide 8 opioid receptor antagonists. J. Med. Chem. 1988, 31, 281-282.
5. Pert, C. B., Bowie, D. L.; Pert, A.; Morell, J. L.; Gross, E. Agonist-antagonist properties of N-allyl-[D-Ala]2-Met-enkephalin. Nature 1977, 269, 73-75.
6. Summers, M. C.; Hayes, R. J. The interaction of N alpha-alkylenkephalins with opiate receptors. Tissue-dependent shifts in the opiate activity of methionine-enkephalin following N alpha-alkylation. J. Biol. Chem. 1981, 256, 4951-4956.
7. Shaw, J. S.; Miller, L.; Turnbull, M.J.; Gormley, J. J.; Morley, J. S. Selective antagonists at the opiate δ-receptor. Life Sci. 1982, 31, 1259-62.
8. Belton, P.; Cotton, R.; Giles, M. B.; Gormley, J. J.; Miller, L.; Shaw, J. S.; Timms, D.; Wilkinson, A. Divergent structure activity relationships in series of enkephalin agonists and cognate antagonists. Life Sci 1983, 33 Suppl. 1, 443-446.
9. Cotton, R.; Giles, M.G.; Miller, L.; Shaw, J. S.; Timms, D. ICI 174864: a highly selective antagonist for the opioid δ -receptor. Eur. J. Pharmacol. 1984, 97, 331-332.
10. Lovett, J. A.; Portoghese, P. S. Synthesis and evaluation of melphalan-containing N,N-dialkylenkephalin analogues as irreversible antagonists of the δ opioid receptor. J. Med. Chem. 1987, 30, 1668-1674.
11. Ronai, A. Z.; Botyanszki, J.; Magyar, A.; Borsodi, A.; Benyhe, S.; Medzihradsky, K. Novel δ-opioid receptor-selective peptide antagonists: demonstration of a possible opioid interaction in the absence of a protonated nitrogen and attempts to locate the protonated nitrogen site. Arch. Int. Pharmacodyn. 1993, 323, 114-125.
12. Lemaire, S.; Turcotte, A. Synthesis and biological activity of analogs of dynorphin-A(1-13) substituted in positions 2 and 4: design of [Ala2,Trp4]-dynorphin -A(1-13) as a putative selective opioid antagonist. Can. J. Physiol. Pharmacol. 1986, 64, 673-678.
13. Gairing, J. E.; Mazarguil, H.; Alvinerie, P.; Saint-Pierre, S.; Meunier, J. C.; Cros, J. Synthesis and biological activities of dynorphin A analogues with opioid actagonist properties J. Med. Chem. 1986, 29, 1913-1917.
14. 10]dynorphin A(1-11) Br. J. Pharmacol. 1988, 95, 1023-1030.
15. Soderstrom, K.; Choi, H.; Berman, F. W.; Aldrich, J. V.; Murray, T. F. N-alkylated derivatives of [D-Pro10]dynorphin A (1-11) are high affinity partial agonists at the cloned rat kappa-opioid receptor. Eur., J. Pharmacol. 1997, 338, 191-197.
16. Choi, H.; Murray, T. F.; DeLander, G. E.; Schmidt, W. K.; Aldrich, J. V. Synthesis and opioid activity of [D-Pro10]dynorphin A (1-11), analogues with N-terminal alkyl substitution. J. Med Chem. 1997, 40, 2733-2739.
17. Wan, Q; Murray, T. F.; Aldrich, J. V. A novel acetylated analogue of dynorphin A (1-11) amide as a kappa-opioid receptor antagonist. J. Med. Chem. 1999, 42, 3011-3013
18. Dooley, C. T.; Chung, N. N.; Schiller, P. W.; Houghten, R. A. Acetalins: opioid receptor antagonists determined through the use of synthetic peptide combinatorial libraries. Proc. Natl. Acad. Sci. USA 1993, 90, 10811-10815.
19. Dooley, C. T.; Kaplan, R. A.; Chung, N. N.; Schiller, P. W.; Bidlack, J. M.; Houghten, R. A. Six highly active μ-selective opioid peptides identified from two synthetic combinatorial libraries.Pept. Res. 1995, 8, 124-137.
20. Schmidt, R; Vogel, D.; Mrestani-Klaus, C.; Brandt, W.; Neubert, K.; Chung, N. N.; Lemieux, C.; Schiller, P. W. Cyclic beta-casomorphin analogues with mixed μ agonist/δ antagonist properties: synthesis, pharmacological characterization, and conformational aspects. J. Med Chem. 1994, 37, 1136-1144.
21. Kramer, T. H.; Shook, J. E.; Kazmierski, W.; Ayres, E.A.; Wire, W. S.; Hruby, V. J.; Burks, T. F. Novel peptidic μ opioid antagonists: pharmacologic characterization in vitro and in vivo. J. Pharmacol. Exp. Ther. 1989, 249, 544-551.
22. Schiller, P. W.; Nguyen, T. M.-D.; Weltrowska, G.; Wilkes, B. C.; Marsden, B. J.; Lemieux, C.; Chung, N.N. Differential stereochemical requirements of μ vs. δ opioid receptors for ligand binding and signal transduction. Development of a class of potent and highly δ -selective peptide antagonists. Proc. Natl. Acad. Sci. USA 1992, 89, 11871-11875.
23. Temussi, P. A.; Salvadori, S.; Amodeo, P.; Bianchi, C.; Guerrini, R.; Tomatis, R.; Lazarus, L. H.; Picone, D.; Tancredi, T Selective Opioid Dipeptides Biochem. Biophys. Res. Commun. 1994, 198, 933 939.
24. Hansen Jr., D. W.; Mazur, R.H.; Clare, M. The synthesis and SAR of orally active enkephalin analogs with modified N-terminal Tyr residue; In Peptides: Structure and Function, Proceedings of the 9th American Peptide Symposium, Toronto, June 23-28, 1985; Deber, C.; M. Hruby, V. J.; Kopple, K. D., Eds; Pierce Chem, Co: Rockford, II, 1985; pp 491-494.
25. Hansen, D. W. Jr; Stapelfeld, A.; Savage, M. A.; Reichman, M.; Hammond, D. L.; Haaseth, R. C.; Mosberg, H. I. Systemic analgesic activity and δ-opioid selectivity in [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5] enkephalin. J. Med. Chem. 1992, 35, 684-687.
26. Chandrakumar, N. S.; Stapelfeld, A.; Beardsley, P. M.; Lopez, O. T.; Drury, B.; Anthony, E.; Savage, M. A.; Williamson, L. N.; Reichman, M. Analogs of the δ opioid receptor selective cyclic peptide [2-D-penicillamine,5-D-penicillamine]-enkephalin: 2′,6′-dimethyltyrosine and Gly3-Phe4 amide bond isostere substitutions. J. Med Chem. 1992, 35, 2928-2938.
27. Salvadori, S.; Attila, M.; Balboni, G.; Bianchi, C.; Bryant, S. D.; Crescenzi, O.; Guerrini, R.; Picone, D.; Tancredi, T.; Temussi P. A.; Lazarus, L. H, Ultraselective δ opioidmimetic dipeptide antagonists. Mol. Med 1995, 1, 678-689.
28. Schiller, P. W.; Weltrowska, G.; Berezowska, I.; Nguyen, T. M.; Wilkes, B. C.; Lemieux, C.; Chung, N. N. The TIPP opioid peptide family: development of δ antagonists, δ agonists, and mixed μ agonist/δ antagonists. Biopolymers 1999, 51, 411-425.
29. Santagada, V.; Caliendo, G.; Severino, B.; Perissutti, E.; Ceccarelli, C.; Giusti, L.; Mazzoni, M. R.; Salvadori, S.; Temussi, P. A. Probing the shape of A Hydrophobic pocket in the active site of δ opioid antagonists J. Pept. Sci. 2001, 7, 374-385.
30. Salvadori, S.; Balboni, G.; Guerrini, R.; Tomatis, R.; Bianchi, C.; Bryant, S. D.; Cooper, P. S.; Lazarus, L. H. Evolution of the Dmt-Tic pharmacophore: N-terminal methylated derivatives with extraordinary δ opioid antagonist activity. J. Med. Chem. 1997, 40, 3100-3108.
31. Schiller, P. W.; Weltrowska, G.; Schmidt, R.; Berezowska, I.; Nguyen, T. M.; Lemieux, C.; Chung, N. N.; Carpenter, K. A.; Wilkes, B. C. Subtleties of structure-agonist versus antagonist relationships of opioid peptides and peptidomimetics. J. Recept. Signal Transduct. Res. 1999, 19, 573-588.
32. Pagè, D.; McClory, A.; Mischki, T.; Schmidt, R.; Butterworth, J.; St-Onge, S.; Labarre, M.; Payza, K.; Brown, W. Novel Dmt-Tic dipeptide analogues as selective δ-opioid receptor antagonists. Bioorg. Med. Chem. Lett. 2000, 10, 167-170.
33. Santagada, V.; Balboni, G.; Caliendo, G.; Guerrini, R.; Salvadori, S.; Bianchi, C.; Bryant, S. D.; Lazarus, L. H. Assessment of substitution in the second pharmacophore of Dmt-Tic analogues. Bioorg. Med. Chem. Lett. 2000, 10, 2745-2748.
34. Salvadori, S.; Guerrini, R.; Balboni, G.; Bianchi, C.; Bryant, S. D.; Cooper, P. S.; Lazarus, L. H. Further studies on the Dmt-Tic pharmacophore: hydrophobic substituents at the C-terminus endow δ antagonists to manifest μ agonism or μ antagonism. J. Med. Chem. 1999, 42, 5010-5019.
35. Balboni, G.; Guerrini, R.; Salvadori, S.; Bianchi, C.; Rizzi, D.; Bryant, S. D., Lazarus, L. H. Evaluation of the Dmt-Tic pharmacophore: conversion of a potent δ-opioid receptor antagonist into a potent δ agonist and ligands with mixed properties. J. Med. Chem. 2002, 45, 713-720.
36. Pagè, D.; Naismith, A.; Schmidt, R.; Coupal, M.; Labarre, M.; Gosselin, M.; Bellemare, D.; Payza, K.; Brown, W. Novel C-terminus modifications of the Dmt-Tic motif: a new class of dipeptide analogues showing altered pharmacological profiles toward the opioid receptors. J. Med. Chem. 2001, 44, 2387-2390.
37. Tancredi, T.; Salvadori, S.; Amodeo, P.; Picone, D.; Lazarus, L. H.; Bryant, S. D.; Guerrini, R.; Marzola, G.; Temussi, P. A. Conversion of Enkephalin and Dermorphin into δ Selective Opioid Antagonists by Single Residue Substitution. Eur. J. Biochem. 1994, 224, 241-247.
38. Guerrini, R.; Capasso, A.; Marastoni, M.; Bryant, S. D.; Cooper, P. S.; Lazarus, L. H.; Temussi, P. A.; Salvadori, S. Rational Design of Dynorphin A Analogues with δ-Receptor Selectivity and Antagonism for δ- and κ-Receptors Biorg. Med. Chem. Lett. 1998, 6, 57-62.
39. Pastore, A.; Temussi, P. A.; Tancredi, T.; Salvadori, S. and Tomatis, R. NMR Studies of Dermorphin and its Peptide Fragments Biopolymers 1984, 23, 2349-2360.
40. Pastore, A.; Temussi, P. A.; Salvadori, S.; Tomatis, R.; Mascagni, P. A Conformational Study of the Opioid Peptide Dermorphin by 1D and 2D NMR Spectroscopy Biophys. J. 1985, 48, 195-202.
41. Castiglione-Morelli, M. A.; Lelj, F.; Pastore, A.; Salvadori, S.; Tancredi, T.; Tomatis, R.; Trivellone, E. and Temussi, P. A. A 500 MHz Study of μ Opiod Peptides in a Simulated Receptor Environment J. Med. Chem. 1987, 30, 2067-2073.
42. Castiglione-Morelli, M. A.; Tancredi, T.; Trivellone, E.; Balboni, G.; Marastoni, M.; Salvadori, S.; Tornatis, R.; Temussi, P. A. SAR of Tetrapeptides related to Dermorphin Biopolymers 1988, 27, 1353-1358.
43. Castiglione-Morelli, M. A.; Saviano, G.; Temussi, P. A.; Balboni, G.; Salvadori, S.; Tomatis, R. NMR Studies of a series of Dehydrodermorphins. Biopolymers 1989, 28, 129-138.
44. Temussi, P. A.; Picone, D.; Tancredi, T.; Tornatis, R.; Salvadori, S.; Marastoni, M.; Balboni, G. Conformational Properties of Deltorphin FEBS Lett. 1989, 247, 283-298.
45. Balboni, G; Marastoni, M.; Picone, D.; Salvadori, S.; Tancredi, T.; Temussi, P. A.; Tomatis, R. New features of the δ opioid receptor: Conformational properties of deltorphin I analogues Biochem. Biophys. Res. Commun 1990, 169, 617-622.
46. Tancredi, T.; Temussi, P. A.; Picone, D.; Amodeo, P.; Tomatis, R.; Salvadori, S.; Marastoni, M.; Santagada, V. and Balboni; G. New insights on μ/δ selectivity of opioid peptides.: Conformational analysis of deltorphin analogues. Biopolymers 1991, 31, 751-760.
47. Temussi, P. A.; Picone, D.; Saviano, G.; Amodeo, P.; Motta, A.; Tancredi, T.; Salvadori, S.; Tomatis, R., Conformational Analysis of an Opioid Peptide in Solvent Media that mimic Cytoplasm Viscosity. Biopolymers 1992, 32, 367-372.
48. Amodeo, P.; Motta, A.; Tancredi, T.; Salvadori, S.; Tomatis, R.; Picone, D.; Saviano, G.; Temussi, P. A. Solution Structure of Deltorphin I at 265 K: A Quantitative NMR Study. Peptide Research 1992, 4, 48-55.
49. Ciajolo, M. R.; Balboni, G.; Picone, D.; Salvadori, S.; Tancredi, T.; Temussi, P. A.; Tuzi, A. Solution and solid state structure of the diketopiperazine of tyrosyl- tetrahydroisoquinoline-3-carboxylic acid Int. J. Peptide Prot. Res. 1995, 46, 134-138.
50. Amodeo, P.; Balboni, G.; Crescenzi, O.; Guerrini, R.; Picone, D.; Salvadori, S.; Tancredi, T.; Temussi, P. A. Conformational Analysis of Potent and Very Selective δOpioid Dipeptide Antagonists FEBS Lett. 1995, 377, 363-367.
51. Crescenzi, O.; Amodeo, P.; Cavicchioni, G.; Guerrini, R.; Picone, D.; Salvadori, S.; Tancredi, T.; Temussi, P. A. 8 Selective Opioid Peptides Containing a Single Aromatic Residue in the Message Domain. A NMR Conformational Analysis J. Pept. Sci. 1996, 2, 290-308.
52. Capasso, A.; Guerrini, R.; Balboni, G.; Sorrentino, L.; Temussi, P. A.; Lazarus, L. H.; Bryant, S. D.; Salvadori, S. Dilit-Tic-OH, a highly selective and potent δ-opioid dipeptide receptor antagonist after systemic administration in tile mouse Life Sciences 1996, 59, PL93-98.
53. Crescenzi, O.; Fraternali, F.; Picone, D.; Tancredi, T.; Balboni, G.; Guerrini, R.; Lazarus, L. H.; Salvadori, S.; Temussi, P. A. Models of Antagonism. Design and Solution Structure of a Partially Rigid Opioid Antagonist Lacking the Basic Center. Eur. J. Biochem. 1997, 247, 66-73.
54. Salvadori, S.; Picone, D.; Tancredi, T.; Guerrini, R.; Spadaccini, R.; Lazarus, L. H.; Regoli, D.; Temussi, P. A. Comparison between the Conformational State and Biological Function of Nociceptin and Dynorphin A. Biochem. Biophys. Res. Commun. 1997, 233, 640-643.
55. Guerrini, R., Rizzi, A.; Bianchi, C., Lazarus, L.H; Salvadori, S., Temussi, P. A.; Regoli, D. Address and message sequences for the nociceptin receptor: a structure-activity study of nociceptin-(1-13)-peptide amide. J. Med. Chem. 1997, 40, 1789-1793.
56. Capasso, A.; Amodeo, P.; Guerrini, R.; Balboni, G.; Lazarus, L. H.; Temussi, P, A.; Salvadori, S. Design of μ selective opioid dipeptide antagonists. FEBS Lett. 1997, 417, 141-144.
57. 15N-Leu-enkephalin. J. Pept. Sci. 1998, 4, 253-265.
58. Crescenzi, O.; Guerrini, R.; Picone, D.; Salvadori, S.; Tancredi, T.; Temussi, P. A. Solution structure of nocistatin, a new peptide analgesic. Biopolymers 2000, 53, 257-264.
59. Amodeo, P.; Lopez Mendez, B.; Guerrini, R.; Salvadori, S.; Temussi, P. A.; Tancredi, T. Pain peptides. Solution structure of orphanin FQ2. FEBS Lett. 2000, 473, 157-60.
60. Spadaccini, R.; Temussi, P. A. Natural peptide analgesics: the role of solution conformation CMLS 2001, 58, 1572-1582.
61. Amodeo, P.; Guerrini, R.; Picone, D.; Salvadori, S.; Spadaccini, R.; Tancredi, T.; Temussi, P. A. Solution Structure of Nociceptin Peptides. J. Pept. Sci. 2002, 8, 497-509.
62. Nyberg, F.; Brantl, V. Proceedings from the First International Symposymn on β-casomorphins and related peptides, Upsala, Sweden. 1989; pp. 15-20.
63. Portoghese, P. S. The role of concepts in structure-activity relationship studies of opioid ligands. J. Med. Chem. 1992, 35, 1927-1937.
64. i opioid receptor agonists and antagonists. J. Med. Chem. 1993, 36, 2572-2574.
65. Mosberg, H. I.; Lomize, A. L.; Wang, C.; Kroona, H.; Heyl, D. L.; Sobezyk-Kojiro, K.; Ma, W.; Mousigian, C.; Porreca; F. Development of a model for the δ opioid receptor pharmacophore. 1. Conformationally restricted Tyr1 replacements in the cyclic δ receptor selective tetrapeptide Tyr-c[D-Cys-Phc-D-Pen]OH (JOM-13). J. Med. Chem. 1994, 37, 4369-4383.
66. Mosberg, H. I.; Omnaas, J. R.; Lomize, A. L.; Heyl, D. L.; Nordan, I.; Mousigian, C.; Davis, P.; Porreca, F. Development of a model for the δ opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the cyclic δ receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13). J. Med. Chem. 1994, 37, 4384-4391.
67. Lomize, A. L.; Mosberg, H. I.; Pogozheva, I. D. Development of a model for the δ opioid receptor pharmacophore: 3. Comparison of the cyclic tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH with other conformationally constrained δ receptor selective ligands. Biopolymers 1996, 38, 221-234.
68. Kong, H.; Raynor, K.; Yasuda, K.; Moe, S. T.; Portoghese, P. S.; Bell, G. I.; Reisine, T. A single residue, aspartic acid 95, in the δ opioid receptor specifies selective high affinity agonist binding. J. Biol. Chem. 1993, 268, 23055-23058.
69. Lu, Y.; Weltrowska G.; Lemieux, C.; Chung, N. N.; Schiller, P. W. Stereospecific synthesis of (2S)-2-methyl-3-(2′,6′-dimethyl-4′-hydroxyphenyl -propionic acid (Mdp) and its incorporation into an opioid peptide. Bioorg. Med. Chem. Lett. 2001, 11, 323-325.
70. 2 analogues lacking an N-terminal amino group: potent and selective kappa opioid antagonists. J. Med. Chem. 2001, 44, 3048-3053.
71. Meunier, J-C.; Mollereau, C.; Toll, L.; Suaudeau, C.; Moisand, C.; Alvinerie, P.; Butour, J-L.; Guillemot, J-C.; Ferrara, P.; Monsarrat, B.; Mazargull, H.; Vassart, G.; Parmentier, M.; Costentin, J. Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 1995, 377, 532-535.
72. Reinscheid, R. K.; Nothacker, H. P.; Bourson, A.; Ardati, A.; Henningse, R. A.; Bunzow, J. R.; Grandy, D. K.; Langen, H.; Monsma, F. Jr; Civelli, O. Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science 1995, 270, 792-794.
73. Meunier, J. C. Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor. Eur. J. Pharmacol. 1997, 340, 1-15.
74. Civelli, O.; Nothacker, H. P.; Reinscheid, R. Reverse physiology: discovery ofthe novel neuropeptide, orphanin FQ/nociceptin. Crit. Rev. Neurobiol. 1998, 12, 163-176.
75. Calo', G.; Guerrini, R.; Rizzi, A.; Salvadori, S.; Regoli, D. Pharmacology of Nociceptin and Its Receptor: A Novel Therapeutic Target. Br. J. Pharmacol. 2000, 129, 1261-1293.
76. Henderson, G.; McKnight, A. T. The orphan opioid receptor and its endogenous ligand - nociceptin/orphanin FQ. Trends Pharmacol. Sci. 1997, 18, 293-300.
77. 2 N-terminal tetrapeptide and discovery of a nociceptin receptor antagonist. J. Med. Chem. 1998, 41, 3360-3366.
78. Meyer, J. P.; Davis, P.; Lee, K. B.; Porreca, F.; Yamamura, H. I.; Hruby, V. J. Synthesis using a Fmoc-based strategy and biological activities ofsome reduced peptide bond pseudopeptide analogues of dynorphin A1. J. Med. Chem. 1995, 38, 3462-3468.
79. 2NH) Chem. Pharm. Bull. 1995, 43, 1547-1550.
80. Guerrini, R.; Calo', G.; Bigoni, R.; Rizzi, A.; Varani, K.; Toth, G.; Gessi, S.; Hashiba, E.; Hashimoto, Y.; Lambert, D.G.; Borea, P.A.; Tomatis, R.; Salvadori, S.; Regoli, D. Further studies on nociceptin-related peptides: discovery of a new chemical template with antagonist activity oil the nociceptin receptor. J. Med. Chem. 2000, 43, 2805-2813.
81. Kirby, G. W. Biosynthesis ofthe morphine alkaloids. Science 1967, 155, 170-173.
82. Fraternali, F.; Anselmi, C.; Temussi, P. A. Neurologically active plant compounds and peptide hormones: a chirality connection. FEBS Lett. 1999, 448, 217-220.
83. Erspamer, V.; Erspamer-Falconieri, G.; Melchiorri, P.; Negri, L.; Corsi, R.; Severini, C.; Barra, D.; Simmaco, M.; Kreil, G. Deltorphins: a family of naturally occurring peptides with high affinity and selectivity for δ opioid binding sites. Proc. Natl. Acad. Sci. USA 1989, 86, 5188-5193.
84. Wechselberger, C.; Severini, C.; Kreil, G.; Negri, L. A new opioid peptide predicted from cloned cDNAs from skin of Pachymedusa dacnicolor and Agalychnis annae. FEBS Lett. 1997, 429, 41-43.
85. Portoghese P. S., Bivalent ligands and the message-address concept in the design of selective opioid receptor antagonists. Trends Pharmacol. Sci. 1989, 10, 230-235
86. Hawkins, K. N.; Knupp, R. J.; Lui, G. K.; Gulya, K.; Kazmierski, W.; Wan, Y. P.; Pelton, J. T.; Hruby, V. J.; Yamamura, H.I. [3H]-[H-D-Phe-Cys-Tyr-D-Trp-Oril-Thr-Pen-Thr-NH2]([3H]CTOP), a potent and highly selective peptide for μ opioid receptors in rat brain. J. Pharmacol. Exp. Ther. 1989, 248, 3-80.