Development of opioid peptide analogs for pain relief

Current Pharmaceutical Design

Volumn 16, Issue 9, 2010, Pages 1126-1135

  Janecka, A ^a   Perlikowska, R ^a   Gach, K ^a   Wyrebska A ^a   Fichna, J ^a  

^a MEDICAL UNIVERSITY OF LODZ   (Poland)

Author keywords

[No Author keywords available]

Indexed keywords

(2',6' DIMETHYLTYROSINE)TYROSINE DEXTRO ARGINYLPHENYLALANYLLYSINAMIDE; BETA CASOMORPHINE DERIVATIVE; BETA ENDORPHIN; BOVINE BETA CASOMORPHINE 7; CR 665; CR 845; DELTA OPIATE RECEPTOR AGONIST; DELTORPHIN; DELTORPHIN 1; DELTORPHIN 2; DERMORPHIN; DEXTRO PHENYLALANINE DEXTRO PHENYLALANINE DEXTRO LEUCINE DEXTRO ORNITHINE MORPHILINE AMIDE; DEXTRO PHENYLALANINE DEXTRO PHENYLALANINE DEXTRO NORLEUCINE DEXTRO ARGININAMIDE; DYNORPHIN A; DYNORPHIN A [1-8][1 (N METHYLTYROSINE) 2 DEXTRO ALANINE 7 ARGININE 6 ARGININE PSI ETHYLAMIDE]; DYNORPHIN A [1-8][1 (N METHYLTYROSINE) 7 (N METHYLARGININE) 8 DEXTRO LEUCINE N ETHYLAMIDE]; DYNORPHIN B; ENDOMORPHIN 1; ENDOMORPHIN 2; FE 200665; FE 200666; KAPPA OPIATE RECEPTOR; KAPPA OPIATE RECEPTOR AGONIST; LEUCINE ENKEPHALIN; METENKEPHALIN; MORPHICEPTIN; MORPHINE; MU OPIATE RECEPTOR; OPIATE PEPTIDE; OPIATE RECEPTOR; PROTEINASE; SK 9709; TYROSINE DEXTRO ARGINYLPHENYLALANYLYSINAMIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

AMINO ACID SEQUENCE; ANALGESIA; ANALGESIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; BLOOD BRAIN BARRIER; CENTRAL NERVOUS SYSTEM; CENTRAL NERVOUS SYSTEM DISEASE; DIFFUSION; DISEASE SEVERITY; DRUG BIOAVAILABILITY; DRUG BRAIN LEVEL; DRUG DESIGN; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; GASTROINTESTINAL SYMPTOM; HUMAN; HYDROPHILICITY; INTESTINE TRANSIT TIME; MUCOSA INFLAMMATION; NEUROMODULATION; NOCICEPTION; NONHUMAN; PAIN; POSTOPERATIVE PAIN; PRIORITY JOURNAL; PROTEIN DEGRADATION; RECEPTOR AFFINITY; RESPIRATION DEPRESSION; REVIEW; SIDE EFFECT; SKIN ULCER; UNSPECIFIED SIDE EFFECT;

AMINO ACID SEQUENCE; ANALGESICS, OPIOID; ANIMALS; DRUG DELIVERY SYSTEMS; DRUG DISCOVERY; HUMANS; OPIOID PEPTIDES; PAIN; RECEPTORS, OPIOID; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77950190490     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/138161210790963869     Document Type: Review

References (149)

1. Olson GA, Olson RD, Vaccarino AL, Kastin AJ. Endogenous opiates: 1997. Peptides 1998; 19: 1791-1843
2. Reisine T, Bell GI. Molecular biology of opioid receptors. Trends Neurosci 1993; 16: 506-510
3. Harrison LM, Kastin AJ, Zadina JE. Opiate tolerance and dependence: receptors, G-proteins, and antiopiates. Peptides 1998; 19: 1603-1630
4. Kieffer BL. Opioids: first lessons from knockout mice. Trends Pharmacol Sci 1999 ; 20 : 19-26.
5. Pasternak GW. Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 1993; 16: 1-18.
6. Zimmerman DM, Leander JD. Selective opioid receptor agonists and antagonists: research tools and potential therapeutic agents. J Med Chem 1990; 33: 895-902.
7. Zadina JE, Kastin AJ, Ge LJ, Hackler L. Mu, delta, and kappa opiate receptor binding of Tyr-MIF-1 and of Tyr-W-MIF-1, its active fragments, and two potent analogs. Life Sci 1994; 55: 461-466
8. Mansour A, Watson SJ. In: Handbook of experimental pharmacology 104/1. Berlin: Springer 1993; pp. 79-105.
9. Wittert G, Hope P, Pyle D. Tissue distribution of opioid receptor gene expression in the rat. Biochem Biophys Res Commun 1996; 218: 877-881
10. Bodnar RJ, Klein GE. Endogenous opiates and behavior: 2004. Peptides 2005; 26: 2629-2711
11. Minami M, Satoh M. Molecular biology of the opioid receptors: structures, functions and distributions. Neurosci Res 1995; 23: 121-145
12. Fichna J, Janecka A. Opioid peptides in cancer. Cancer Metast Rev 2004; 23: 351-366
13. Rossi GC, Leventhal L, Pan YX, Cole J, Su W, Bodnar RJ, et al. Antisense mapping of MOR-1 in rats: distinguishing between morphine and morphine-6-β-glucuronide antinociception. J Pharmacol Exp Ther 1997; 281: 109-114
14. Sánchez-Blázquez P, García-Espãna A, Garzón J. Antisense oligodeoxynucleotides to opioid μ and Δ receptors reduced morphine dependence in mice: role of Δ-2 opioid receptors. J Pharmacol Exp Ther 1997; 280: 1423-1431
15. Joshi SK, Su X, Porreca F, Gebhart GF. κ-opioid receptor agonists modulate visceral nociception at a novel, peripheral site of action. J Neurosci 2000; 20: 5874-5879
16. Janecka A, Fichna J, Janecki T. Opioid receptors and their ligands. Curr Top Med Chem 2004; 4: 1-17.
17. Fichna J, Janecka A, Costentin J, Do Rego JC. The endomorphin system and its evolving neurophysiological role. Pharmacol Rev 2007; 59: 88-123.
18. Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975; 258: 577-580
19. Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L. Dynorphin-(1-13), an extraordinarily potent opioid peptide. Proc Natl Acad Sci USA 1979; 76: 6666-6670
20. Chavkin C, James IF, Goldstein A. Dynorphin is a specific endogenous ligand of the κ opioid receptor. Science 1982; 215: 413-415
21. Li CH, Chung D. Isolation and structure of an untriakontapeptide with opiate activity from camel pituitary glands. Proc Natl Acad Sci USA 1976; 73: 1145-1148
22. Zadina JE, Hackler L, Ge LJ, Kastin AJ. A potent and selective endogenous agonist for the mu-opiate receptor. Nature 1997; 386: 499-502.
23. Brantl V, Teschemacher H, Henschen A, Lottspeich F. Novel opioid peptides derived from casein (beta-casomorphins). I. Isolation from bovine casein peptone. Hoppe-Seyler's Z Physiol Chem 1979; 360: 1211-1216
24. 2): a potent and specific agonist for morphine (μ) receptors. Science 1981; 212: 75-77
25. Chang KJ, Su IF, Brent DA, Chang JK. Isolation of a specific muopiate receptor peptide, morphiceptin, from an enzymatic digest of milk proteins. J Biol Chem 1985; 250: 9706-9712
26. Teschemacher H. Atypical opioid peptides. In: Handbook of experimental pharmacology 104/I, Opioids I. Berlin: Springer-Verlag 1993; pp. 499-528.
27. Montecucchi PC, de Castiglione R, Piani S, Gozzini L, Erspamer V. Amino acid composition and sequence of dermorphin, a novel opiate-like peptide from the skin of Phyllomedusa sauvagei. Int J Peptide Protein Res 1981; 17: 275-283
28. Kreil G, Barra D, Simmaco M, Erspamer V, Falconieri-Erspamer G, Negri L, et al. Deltorphin, a novel amphibian skin peptide with high selectivity and affinity for Δ opioid receptors. Eur J Pharmacol 1989; 162: 123-128
29. 2] deltorphin, a 17 amino acid opioid peptide from the skin of the brazilian hylid frog, Phyllomedusa burmeisteri. Peptides 1994; 15: 199-202.
30. 2): a potent and fully specific agonist for the delta opioid receptor. Mol Pharmacol 1989; 35: 774-779
31. Yamazaki T, Ro S, Goodman M, Chung NN, Schiller PW. A topochemical approach to explain morphiceptin bioactivity. J Med Chem 1993; 36: 708-719
32. Goldberg IE, Rossi GC, Letchworth SR, Mathis JP, Ryan-Moro J, Leventhal L, et al. Pharmacological characterization of endomorphin-1 and endomorphin-2 in mouse brain. J Pharmacol Exp Ther 1998; 286: 1007-1013
33. Stone LS, Fairbanks CA, Laughlin TM, Nguyen HO, Bushy TM, Wessendorf MW, et al. Spinal analgesic actions of the new endogenous opioid peptides endomorphin-1 and -2. Neuroreport 1997; 8: 3131-3135
34. Przewłocka B, Mika J, Labuz D, Toth G, Przewłocki R. Spinal analgesic action of endomorphins in acute, inflammatory and neuropathic pain in rats. Eur J Pharmacol 1999; 367: 189-196
35. Horvath G, Szikszay M, Tomboly C, Benedek G. Antinociceptive effects of intrathecal endomorphin-1 and -2 in rats. Life Sci 1999; 65: 2635-2641
36. Tseng LF, Narita M, Suganuma C, Mizoguchi H, Ohsawa M, Nagase H, et al. Differential antinociceptive effects of endomorphin-1 and endomorphin-2 in the mouse. J Pharmacol Exp Ther 2000; 292: 576-583
37. Soignier RD, Vaccarino AL, Brennan AM, Kastin AJ, Zadina JE. Analgesic effects of endomorphin-1 and endomorphin-2 in the formalin test in mice. Life Sci 2000; 67: 907-912
38. Chavkin C, Goldstein A. Specific receptor for the opioid peptide dynorphin: structure-activity relationships. Proc Natl Acad Sci USA 1981; 78: 6543-6547
39. Leslie FM, Goldstein A. Degradation of dynorphin (1-13) by membrane-bound rat enzymes. Neuropeptides 1982; 2: 185-196
40. Brugos B, Hochhaus G. Metabolism of dynorphin A(1-13). Pharmazie 2004; 59: 339-343
41. Reed B, Zhang Y, Chait BT, Kreek MJ. Dynorphin A(1-17) biotransformation in striatum of freely moving rats using microdialysis and matrix-assisted laser desorption/ionization mass spectrometry. J Neurochem 2003; 86: 815-823
42. Vanhoof G, Goossens F, De Meester I, Hendriks D, Scharpé S. Proline motifs in peptides and their biological processing. FASEB J 1995; 9: 736-744
43. Cunningham DF, O'Connor B. Proline specific peptidases. Biochim Biophys Acta 1997; 1343: 160-186
44. Janecka A, Staniszewska R, Gach K, Fichna J. Enzymatic degradation of endomorphins. Peptides 2008; 29: 2066-2073
45. Sakurada C, Sakurada S, Hayashi T, Katsuyama S, Tan-No K, Sakurada T Degradation of endomorphin-2 at the supraspinal level in mice is initiated by dipeptidyl peptidase IV: an in vitro and in vivo study. Biochem Pharmacol 2003; 66: 653-661
46. Shane R, Wilk S, Bodnar RJ. Modulation of endomorphin-2-induced analgesia by dipeptidyl peptidase IV. Brain Res 1999; 815: 278-286
47. Tomboly C, Peter A, Toth G. In vitro quantitative study of the degradation of endomorphins. Peptides 2002; 23:1573-1580
48. Guieu R, Fenouillet E, Devaux C, Fajloun Z, Carrega L, Sabatier JM, et al. CD26 modulates nociception in mice via its dipeptidylpeptidase IV activity. Behav Brain Res 2006; 166: 230-235
49. Ambler RP. Carboxypeptidases A and B. Methods Ezymol 1972; 25: 262-272
50. Peter A, Toth G, Tomboly C, Laus G, Tourwe D. Liquid chromatographic study of the enzymatic degradation of endomorphins, with identification by electrospray ionization mass spectrometry. J Chromatogr A 1999; 846: 39-48.
51. Cardillo G, Gentilucci L, Qasem AR, Sgarzi F, Spampinato S. Endomorphin-1 analogues containing beta-proline are μ-opioid receptor agonists and display enhanced enzymatic hydrolysisr. J Med Chem 2002; 45: 2571-2578
52. Gentilucci L. New trends in the development of opioid peptide analogues as advanced remedies for pain relief. Curr Top Med Chem 2004; 4: 19-38.
53. Begley DJ. The blood-brain barrier: principles for targeting peptides and drugs to the central nervous system. J Pharm Pharmacol 1996; 48: 136-146
54. Ganapathy V, Miyauchi S. Transport systems for opioid peptides in mammalian tissues. AAPS J 2005; 7: E852-6.
55. Pauletti GM, Gangwar S, Siahaan TJ, Jeffrey Aubé, Burchardt RT. Improvement of oral peptide bioavailability: peptidomimetics and prodrug strategies. Adv Drug Deliv Rev 1997; 27: 235-256
56. Pauletti GM, Okumu FW, Borchardt RT. Effect of size and charge on the passive diffusion of peptides across Caco-2 cell monolayers via the paracellular pathway. Pharm Res 1997; 14: 164-168
57. Levin VA. Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 1980; 23: 682-684
58. Pardridge W. CNS drug design based on principles of blood-brain barrier transport. J Neurochem 1998; 70: 1781-1792
59. Pardridge W. Blood-brain barrier biology and methodology. J Neurovirol 1999; 5: 556-569
60. Matsunaga TO, Collins N, Ramaswami V, Yamamura SH, O'Brien DF, Hruby VJ. Comparison of the membrane-bound states of two structurally similar Δ-selective opioid peptides by transferred nuclear Overhauser effect spectroscopy and molecular modeling. Biochemistry 1993; 32: 13180-13189
61. Ramaswami V, Haaseth RC, Matsunaga TO, Hruby VJ, O'Brien DF. Opioid peptide interactions with lipid bilayer membranes. Biochim Biophys Acta 1992; 1109: 195-202.
62. Burton PS, Conradi RA, Ho NF, Hilgers AR, Borchardt RT. How structural features influence the biomembrane permeability of peptides. J Pharm Sci 1996; 85: 1336-1340
63. Polt R, Dhanasekaran M, Keyari CM. Glycosylated neuropeptides: a new vista for neuropsychopharmacology? Med Res Rev 2005; 25: 557-585
64. Witt K, Gillespie TJ, Huber JD, Egleton RD, Davis TP. Peptide drug modifications to enhance bioavailability and blood-brain barrier permeability. Peptides 2001; 22: 2329-2343
65. Temsamani J, Scherrmann JM, Rees AR, Kaczorek M. Brain drug delivery technologies: novel approaches for transporting therapeutics. Pharm Sci Technol Today 2000; 2: 49-59.
66. Liu HM, Liu XF, Yao JL, Wang CL, Yu Y, Wang R. Utilization of combined chemical modifications to enhance the blood-brain barrier permeability and pharmacological activity of endomorphin-1. J Pharmacol Exp Ther 2006; 319: 308-316
67. Bak A, Gudmundsson OS, Friis GJ, Siahaan TJ, Borchardt RT. Acyloxyalkoxy-based cyclic prodrugs of opioid peptides: evaluation of the chemical and enzymatic stability as well as their transport properties across Caco-2 cell monolayers. Pharm Res 1999; 16: 24-29
68. Uchiyama T, Kotani A, Tatsumi H, Kishida T, Okamoto A, Okada N, et al. Development of novel lipophilic derivatives of DADLE (leucine enkephalin analogue): intestinal permeability characateristics of DADLE derivatives in rats. Pharm Res 2000; 17: 1461-1467
69. 5]enkephalin opioid analogs. J Pharmacol Exp Ther 1993; 266: 1649-1655
70. Dygos JH, Yonan EE, Scaros MG, Goodmonson OJ, Getman DP, Periana RA, et al. A convenient asymmetric synthesis of the unnatural amino acid 2,6-dimethyl-L-tyrosine. Synthesis 1992; 8: 741-743
71. Bryant S, Jinsmaa Y, Salvadori S, Okada Y, Lazarus LH. Dmt and opioid peptides: a potent alliance. Biopolymers 2003; 71: 86-102.
72. Wong A, Toth I. Lipid, sugar and liposaccharide based delivery systems. Curr Med Chem 2001; 8: 1123-1136
73. Hardebo JE, Hardebo JE, Kahrström J. Endothelial negative surface charge areas and blood-brain barrier function. Acta Physiol Scand 1985; 125: 495-499
74. Pardridge WM, Boado RJ, Kang YS. Vector-mediated delivery of a polyamide ("peptide") nucleic acid analogue through the blood-brain barrier in vivo. Proc Natl Acad Sci U S A 1995; 92: 5592-5596
75. Chakrabarti S, Sima AA. The presence of anionic sites in basement membranes of cerebral capillaries. Microvasc Res 1990; 39: 123-127
76. Terasaki T, Hirai K, Sato H, Kang YS, Tsuji A. Absorptivemediated endocytosis of a dynorphin-like analgesic peptide, E-2078 into the blood-brain barrier. J Pharmacol Exp Ther 1989; 251: 351-357
77. Yu J, Butelman ER,. Woods JH, Chait BT, Kreek MJ. Dynorphin A (1-8) analog, E-2078, crosses the blood-brain barrier in rhesus monkeys. J Pharmacol Exp Ther 1997; 282: 633-638
78. Hau V, Huber JD, Campos CR, Lipkowski AW, Misicka A, Davis TP. Effect of guanidino modification and proline substitution on the in vitro stability and blood-brain barrier permeability of endomorphin II. J Pharm Sci 2002; 91: 2140-2149
79. Egleton R, Mitchell SA, Huber JD, Janders J, Stropova D, Polt R, et al. Improved bioavailability to the brain of glycosylated Metenkephalin analogs. Brain Res 2000; 881: 37-46.
80. Bilsky EJ, Egleton RD, Mitchell SA, Palian MM, Davis P, Huber JD, et al. Enkephalin glycopeptide analogues produce analgesia with reduced dependence liability. J Med Chem 2000; 43: 2586-2590
81. Negri L, Lattanzi R, Tabacco F, Orrù L, Severini C, Scolaro B, et al. Dermorphin and deltorphin glycosylated analogues: synthesis and antinociceptive activity after systemic administration. J Med Chem 1999; 42: 400-404
82. Tomatis R, Marastoni M, Balboni G, Guerrini R, Capasso A, Sorrentino L, et al. Synthesis and pharmacological activity of deltorphin and dermorphin-related glycopeptides. J Med Chem 1997; 40: 2948-2952
83. Polt R Porreca F, Szabò LZ, Bilsky EJ, Davis P, Abbruscato TJ, et al. Glycopeptide enkephalin analogues produce analgesia in mice: evidence for penetration of the blood-brain barrier. Proc Natl Acad Sci U S A 1994; 91: 7114-7118
84. Powell M, Stewart T, Otvos L, Jr, Urge L, Gaeta FC, Sette A, et al. Peptide stability in drug development. II. Effect of single amino acid substitution and glycosylation on peptide reactivity in human serum. Pharm Res 1993; 10: 1268-1273
85. Fisher J, Harrison AW, Bundy GL, Wilkinson KF, Rush BD, Ruwart MJ. Peptide to glycopeptide: glycosylated oligopeptide renin inhibitors with attenuated in vivo clearance properties. J Med Chem 1991; 34: 3140-3143
86. Law PY, Loh HH. Regulation of opioid receptor activities. J Pharmacol Exp Ther 1999; 289: 607-624
87. Galligan JJ, Mosberg HI, Hurst R, Hruby VJ, Burks TF. Cerebral Δ opioid receptors mediate analgesia but not the intestinal motility effects of intracerebroventricularly administered opioids. J Pharmacol Exp Ther 1984; 229: 641-648
88. Narita M, Funada M, Suzuki T. Regulations of opioid dependence by opioid receptor types. Pharmacol Ther 2001; 89: 1-15.
89. 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: 1261-1283
90. Gavériaux-Ruff C, Kieffer BL. Opioid receptor genes inactivated in mice: the highlights. Neuropeptides 2002; 36: 62-71.
91. Horwell DC. κ opioid analgesics. Drugs Future 1988; 13: 1061-1070
92. Barber A, Gottschlich R. Opioid agonists and antagonists: an evaluation of their peripheral actions in inflammation. Med Res Rev 1992; 12: 525-562
93. Kapitzke D, Vetter I, Cabot PJ. Endogenous opioid analgesia in peripheral tissues and the clinical implications for pain control. Ther Clin Risk Manag 2005; 1: 279-297
94. Janecka A, Staniszewska R, Fichna J. Endomorphin analogs. Curr Med Chem 2007; 14: 3201-3208
95. Schiller PW, Nguyen TM, Chung NN, Lemieux C. Dermorphin analogues carrying an increased positive net charge in their "message" domain display extremely high mu opioid receptor selectivity. J Med Chem 1989; 32: 698-703.
96. Schiller PW, Nguyen TM, Berezowska I, Dupuis S, Weltrowska G, Chung NN, et al. Synthesis and in vitro opioid activity profiles of DALDA analogues. Eur J Med Chem 2000; 35: 895-901.
97. Szeto HH, Lovelace JL, Fridland G, Soong Y, Fasolo J, Wu D, et al. In vivo pharmacokinetics of selective μ-opioid peptide agonists. J Pharmacol Exp Ther 2001; 298: 57-61.
98. Zhao K, Luo G, Zhao GM, Schiller PW, Szeto HH. Transcellular transport of a highly polar 3+ net charge opioid tetrapeptide. J Pharmacol Exp Ther 2003; 304: 425-432
99. Schiller PW. Opioid peptide-derived analgesics. AAPS J 2005; 7: E560-5.
100. Shimoyama M, Shimoyama N, Zhao GM, Schiller PW, Szeto HH. Antinociceptive and respiratory effects of intrathecal H-Tyr-D-Arg-Phe-Lys-NH 2 (DALDA) and [Dmt1]DALDA. J Pharmacol Exp Ther 2001; 297: 364-371
101. 1] DALDA, a highly potent and selective μ-opioid peptide. Eur J Pharmacol 2001; 419: 15-23.
102. 1]DALDA analgesia. Brain Res 2003; 974: 254-257
103. Reimann W, Schlütz H, Selve N. The antinociceptive effects of morphine, desipramine, and serotonin and their combinations after intrathecal injection in the rat. Anesth Analg 1999; 88: 141-145
104. Schiller PW. Bi- or multifunctional opioid peptide drugs. Life Sci 2009, in press, doi:10.1016/j.lfs.2009.02.025.
105. Morphy R, Rankovic Z. Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem 2005; 48: 6523-6543
106. Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 2008; 51: 347-372
107. Ogawa T, Miyamae T, Murayama K, Okuyama K, Okayama T, Hagiwara M, et al. Synthesis and structure-activity relationships of an orally available and long-acting analgesic peptide, Nα-amidino-Tyr-D-Arg-Phe-Me-βAla-OH (ADAMB). J Med Chem 2002; 45: 5081-5089
108. Koda Y, Del Borgo M, Wessling ST, Lazarus LH, Okada Y, Toth I, et al. Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides. Bioorg Med Chem 2008; 16: 6286-6296
109. Mosberg HI, Hurst R, Hruby VJ, Gee K, Yamamura HI, Galligan JJ, et al. Bis-penicillamine enkephalins possess highly improved specificity toward Δ opioid receptors. Proc Natl Acad Sci USA 1983; 80: 5871-5874
110. Gao B, Hagenbuch B, Kullak-Ublick GA, Benke D, Aguzzi A, Meier PJ. Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J Pharmacol Exp Ther 2000; 294: 73-79
111. 5]-enkephalin (DPDPE). J Pharmacol Exp Ther 2001; 298: 848-856
112. Erez M, Takemori AE, Portoghese PS. Narcotic antagonistic potency of bivalent ligands which contain β-naltrexamine. Evidence for bridging between proximal recognition sites. J Med Chem 1982; 25: 847-849
113. Lipkowski AW, Konecka AM, Sroczynska I. Double-enkephalins-synthesis, activity on guinea-pig ileum, and analgesic effect. Peptides 1982; 3: 697-700.
114. Shimohigashi Y, Costa T, Chen HC, Rodbard D. Dimeric tetrapeptide enkephalins display extraordinary selectivity for the delta opiate receptor. Nature 1982; 297: 333-335
115. Abbruscato TJ, Williams SA, Misicka A, Lipkowski A.W, Hruby VJ, Davis TP. Blood-to-central nervous system entry and stability of biphalin, a unique double-enkephalin analog, and its halogenated derivatives. J Pharmacol Exp Ther 1996; 276: 1049-1057
116. Yamazaki M, Suzuki T, Narita M, Lipkowski AW. The opioid peptide analogue biphalin induces less physical dependence than morphine. Life Sci 2001; 69: 1023-1028
117. Abbruscato TJ, Thomas SA, Hruby VJ, Davis TP. Brain and spinal cord distribution of biphalin: correlation with opioid receptor density and mechanism of CNS entry. J Neurochem 1997; 69: 1236-1245
118. Hettiarachchi K, Ridge S, Thomas DW, Olson L, Obi CR, Singh D. Characterization and analysis of biphalin: an opioid peptide with a palindromic sequence. J Pept Res 2001; 57: 151-161
119. Kosson D, Klinowiecka A, Kosson P, Bonney I, Carr DB, Mayzner-Zawadzka E, et al. Intrathecal antinociceptive interaction between the NMDA antagonist ketamine and the opioids, morphine and biphalin. Eur J Pain 2008; 12: 611-616
120. Wojciechowski P, Szereda-Przestaszewska M, Lipkowski AW. Respiratory and cardiovascular effects of biphalin in anaesthetized rats. Eur J Pharmacol 2009; 602: 50-53
121. Abdelhamid E, Sultana M, Portoghese PS, Takemori AE. Selective blockage of Δ opioid receptors prevents the development of morphine tolerance and dependence in mice. J Pharmacol Exp Ther 1991; 258: 299-303.
122. Zhu Y, King MA, Schuller AG, Nitsche JF, Reidl M, Elde RP, et al. Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron 1999; 24: 243-252
123. Schiller PW, Nguyen TM, Weltrowska G, Wilkes BC, Marsden BJ, Lemieux C, et al. Differential stereochemical requirements of m vs delta 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
124. Schiller PW, Fundytus ME, Merovitz L, Weltrowska G, Nguyen TM, Lemieux C, et al. The opioid μ agonist/Δ antagonist DIPPNH(2)[Psi] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats. J Med Chem 1999; 42: 3520-3526
125. Schiller PW, Weltrowska G, Berezowska I, Nguyen TM, Wilkes BC, Lemieux C, et al. The TIPP opioid peptide family: development of Δ antagonists, Δ agonists, and mixed μ agonist/delta antagonists. Biopolymers 1999; 51: 411-425
126. Salvadori S, Trapella C, Fiorini S, Negri L, Lattanzi R, Bryant SD, et al. A new opioid designed multiple ligand derived from the micro opioid agonist endomorphin-2 and the μ opioid antagonist pharmacophore Dmt-Tic. Bioorg Med Chem 2007; 15: 6876-6881
127. Naqvi T, Haq W, Mathur KB. Structure-activity relationship studies of dynorphin A and related peptides. Peptides 1998; 19: 1277-1292
128. Aldrich JV, McLaughlin JP. Peptide κ opioid receptor ligands. Potential for Drug Development. APPS J 2009, DOI: 10.1208/s12248-009-9105-4
129. 10]dynorphin A-(1-11) analogues with N-terminal alkyl substitution. J Med Chem 1997; 40: 2733-2739
130. Butelman ER, Vivian JA, Yu J, Kreek MJ, Woods JH. Systemic effects of E-2078, a stabilized dynorphin A(1-8) analog, in rhesus monkeys. Psychopharmacology (Berl) 1999; 143: 190-196
131. Soderstrom K, Choi H, Berman FW, Aldrich JV, Murray TF. 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
132. Lung F, Meyer JP, Lou BS, Xiang L, Li G, Davis P, et al. Effects of modifications of residues in position 3 of dynorphin A(1-11)-NH2 on kappa receptor selectivity and potency. J Med Chem 1996; 39: 2456-2460
133. Aldrich JV, Zheng Q, Murray TF. Dynorphin A analogs containing a conformationally constrained phenylalanine derivative in position 4: Reversal of preferred stereochemistry for opioid receptor affinity and discrimination of kappa vs. delta receptors. Chirality 2001; 13: 125-129
134. Meyer JP, Gillespie TJ, Hom S, Hruby VJ, Davis TP. In vitro stability of some reduced peptide bond pseudopeptide analogues of dynorphin A. Peptides 1995; 16: 1215-1219
135. 2, in mice. Br J Pharmacol 2001; 132: 1948-1956.
136. Tachibana S, Yoshino H, Arakawa Y, Nakazawa T, Kaneko T, Yamatsu K, et al. In: Takagi H, Ed. Biowarning System in the Brain. Tokyo: Uniwersity of Tokyo Press 1988; pp. 101-109.
137. Nakazawa T, Furuya Y, Kaneko T, Yamatsu K. Spinal κ receptormediated analgesia of E-2078, a systemically active dynorphin analog, in mice. J Pharmacol Exp Ther 1991; 256: 76-81.
138. Terasaki T, Deguchi Y, Sato H, Hirai K, Tsuji A. In vivo transport of a dynorphin-like analgesic peptide, E-2078, through the blood-brain barrier: an application of brain microdialysis. Pharm Res 1991; 8: 815-820
139. Butelman ER, Harris TJ, Kreek MJ. Effects of E-2078, a stable dynorphin A(1-8) analog, on sedation and serum prolactin levels in rhesus monkeys. Psychopharmacology (Berl) 1999; 147: 73-80.
140. Ohnishi A, Mihara M, Yasuda S, Tomono Y, Hasegawa J, Tanaka T. Aquaretic effect of the stable dynorphin-A analog E2078 in the human. J Pharmacol Exp Ther 1994; 270: 342-347
141. 2NH). Chem Pharm Bull 1995; 43: 1547-1550
142. Dooley CT, Ny P, Bidlack JM, Houghten RA. Selective ligands for the μ, Δ, and κ opioid receptors identified from a single mixture based tetrapeptide positional scanning combinatorial library. J Biol Chem 1998; 273: 18848-18856
143. Vanderah T, Schteingart CD, Trojnar J, Junien JL, Lai J, Riviere PJ. FE200041 (D-Phe-D-Phe-D-Nle-D-Arg-NH2): a peripheral efficacious κ opioid agonist with unprecedented selectivity. J Pharmacol Exp Ther 2004; 310: 326-333
144. Binder W, Machelska H, Mousa S, Schmitt T, Rivière PJ, Junien JL, et al. Analgesic and antiinflammatory effects of two novel κ- opioid peptides. Anesthesiology 2001; 94: 1034-1044
145. Vanderah T, Largent-Milnes T, Lai J, Porreca F, Houghten RA, Menzaghi F, et al. Novel D-amino acid tetrapeptides produce potent antinociception by selectively acting at peripheral κ-opioid receptors. Eur J Pharmacol 2008; 583: 62-72.
146. Schteingart CD, Menzaghi F, Jiang G, Alexander RV, Sueiras-Diaz J, Spencer RH, et al. Synthetic peptide amides. US Patent 7,402,564, Cara Therapeutics, Inc. 2008.
147. Berrocoso E, Sanchez-Blazquez P, Garzon J, Mico JA. Opiates as antidepressants. Curr Pharm Des 2009; 15(14): 1612-1622
148. Han TS, Teichert RW, Olivera BM, Bulaj G. Conus venoms - a rich source of peptide-based therapeutics. Curr Pharm Des 2008; 14(24): 2462-2479
149. Norton RS, McDonough SI. Peptides targeting voltage-gated calcium channels. Curr Pharm Des 2008; 14(24): 2480-2491