Oral Bioavailability of a New Class of μ-Opioid Receptor Agonists Containing 3,6-Bis[Dmt-NH(CH2)n]-2(1H)-pyrazinone with Central-Mediated Analgesia

Journal of Medicinal Chemistry

Volumn 47, Issue 10, 2004, Pages 2599-2610

  Jinsmaa, Yunden ^a   Miyazaki, Anna ^b   Fujita, Yoshio ^b   Li, Tingyou ^b   Fujisawa, Yutaka ^b   Shiotani, Kimitaka ^b   Tsuda, Yuko ^b   Yokoi, Toshio ^b   Ambo, Akihiro ^c   Sasaki, Yusuke ^c   Bryant, Sharon D ^a   Lazarus, Lawrence H ^a   Okada, Yoshio ^b  

^a NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES   (United States)

^b KOBE GAKUIN UNIVERSITY   (Japan)

^c TOHOKU PHARMACEUTICAL UNIVERSITY   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

3,6 BIS(2',6' DIMETHYLTYROSINAMINOPROPYL) 5 METHYL 2(1H) PYRAZINONE; ANTINOCICEPTIVE AGENT; DELTA OPIATE RECEPTOR; MU OPIATE RECEPTOR AGONIST; PYRAZINE DERIVATIVE; UNCLASSIFIED DRUG;

ANALGESIA; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINOCICEPTION; AQUEOUS SOLUTION; ARTICLE; BLOOD BRAIN BARRIER; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG POTENCY; HOT PLATE TEST; HYDROPHOBICITY; MOUSE; NONHUMAN; PROTEIN TRANSPORT; RECEPTOR AFFINITY; TAIL FLICK TEST;

ADMINISTRATION, ORAL; ANALGESICS; ANIMALS; BINDING, COMPETITIVE; BIOLOGICAL AVAILABILITY; BRAIN; GUINEA PIGS; ILEUM; INJECTIONS, INTRAVENTRICULAR; INJECTIONS, SUBCUTANEOUS; MALE; METHIONINE; MICE; MODELS, MOLECULAR; PYRAZINES; RECEPTORS, OPIOID, MU; STEREOISOMERISM; SWINE; VAS DEFERENS;

EID: 2342572941     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0304616     Document Type: Article

References (59)

1. 2, negative log of the molar concentration required to double the agonist concentration to achieve the original response; TFA, trifluoroacetic acid; Tic, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; TLC, thin-layer chromatography; Z, benzyloxycarbonyl.
2. (a) Tome, D.; Dumontier, A.-M.; Hautefeuille, M.; Desjeux, J.-F. Opiate activity and transepithelial passage of intact β-casomorphins in rabbit ileum. Am. J. Physiol. 1987, 253, G737-G744.
3. (b) Smith, P. L.; Wall, D. A.; Gochoco, C. H.; Wilson, G. Routes of delivery: case studies. Oral absorption of peptides and proteins. Ad. Drug Delivery Rev. 1992, 8, 253-290.
4. (a) Banks, W. A.; Kastin, A. J. Peptide transport systems for opiates across the blood-brain barrier. Am. J. Physiol. 1990, 259, E1-E10.
5. (b) Ermisch, A.; Brust, P.; Kretzschmar, R.; Ruhle, H.-J. Peptides and blood-brain barrier transport. Physiol. Rev. 1993, 73, 489-527.
6. (c) Begley, D. J. Peptides and the blood-brain barrier: the status of our understanding. Ann. N. Y. Acad. Sci. 1994, 739, 83-100.
7. (a) Yokohama, S.; Yamashita, K.; Toguchi, H.; Takeuchi, J.; Kitamori, N. Absorption of thyrotropin-releasing hormone after oral administration of the TRH tartrate monohydrate in the rat, dog and human. J. Pharm. Dynamics 1984, 7, 101-111.
8. (b) Lundin, S.; Pantzar, N.; Broeders, A.; Ohlin, M.; Westrom, B. R. Differences in transport rate of oxytocin and vasopressin analogues across proximal and distal isolated segments of the small intestine of the rat. Pharm. Res. 1991, 8, 1274-1280.
9. (c) Samii, A.; Bickel, U.; Stroth, U.; Pardridge, W. M. Blood-brain barrier transport of neuropeptides: analysis with a metabolically stable dermorphin analogue. Am. J. Physiol. 1994, 267, E124-E131.
10. Brownson, E. A.; Abbruscato, T. J.; Gillespie, T. J.; Hruby, V. J.; Davis, T. P. Effect of peptidases at the blood brain barrier on the permeability of enkephalin. J. Pharmacol. Exp. Ther. 1994, 270, 675-680.
11. Pantzar, N.; Westrom, B. R.; Luts, A.; Lundin, S. Regional small-intestinal permeability in vitro to different-sized dextrans and proteins in the rat. Scand. J. Gastroenterol. 1993, 28, 205-211.
12. Kreuter, J.; Alyautdin, R. N.; Kharkevich, D. A.; Ivanov, A. A. Passage of peptides through the blood-brain barrier with collodial polymer particles (nanoparticles). Brain Res. 1995, 674, 171-174.
13. 2] Leu-enkephalin derivatives conjugated with the 1-adamantane moiety. Biochem. Pharmacol. 1991, 41, R5-R8.
14. (a) Bundgaard, H. Means to enhance penetration. Prodrugs as a means to improve the delivery of peptide drugs. Ad. Drug Delivery Rev. 1992, 8, 1-38.
15. (b) Bodor, N.; Prokai, L.; Wu, W.-M.; Farag, H.; Jonalagadda, S.; Kawamura, M.; Simpkins, J. A strategy for delivering peptides into the central nervous system by sequential metabolism. Science 1992, 257, 1698-1700.
16. (c) Yang, J. Z.; Chen, W.; Borchardt, R. T. In vitro stability and in vitro pharmacokinetic studies of a model opioid peptide, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE), and its cyclic prodrugs. J. Pharmacol. Exp. Ther. 2002, 303, 840-848.
17. (d) Chen, W.; Yang, J. Z.; Andersen, R.; Nielsen, L. H.; Borchardt, R. T. Evaluation of the permeation characteristics of a model opioid peptide, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE), and its cyclic pro-drugs across the blood-brain barrier using an in situ perfused rat brain model. J. Pharmacol. Exp. Ther. 2002, 303, 849-857.
18. Poduslo, J. F.; Curran, G. L. Glycation increases the permeability of proteins across the blood-nerve and blood-brain barriers. Mol. Brain Res. 1994, 23, 157-162.
19. Polt, R.; Porreca, F.; Szabo, L. Z.; Bilsky, E. J.; Davis, P.; Abbruscato, T. J.; Davis, T. P.; Horvath, R.; Yamamura, H. I.; Hruby, V. J. 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.
20. Bickel, U.; Kang, Y.-S.; Pardridge, W. M. In vivo cleavability of a disulfide-based chimeric opioid peptide in rat brain. Bioconjugate Chem. 1995, 6, 211-218.
21. (a) Schinkel, A. H.; Wagenaar, E.; Mol, C. A. A. M.; van Deemter, L. P-Glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 1996, 97, 2517-2524.
22. (b) Tomatis, R.; Marastoni, M.; Balboni, G.; Guerrini, R.; Capasso, A.; Sorrentino, L.; Santagada, V.; Caliendo, G.; Lazarus, L. H.; Salvadori, S. Synthesis and pharmacological activity of deltorphin and dermorphin-related glycopeptides. J. Med. Chem. 1997, 40, 2948-2952.
23. (c) Negri, L.; Lattanzi, R.; Tabacco, F.; Scolaro, B.; Rocchi, R. Glycodermorphins: opioid peptides with potent and prolonged analgesic activity and enhanced blood-brain barrier penetration. Br. J. Pharmac. 1998, 124, 1516-1522.
24. (d) Negri, L.; Lattanzi, R.; Tabacco, F.; Orru, L.; Severini, C.; Scolaro, B.; Rocchi, R. Dermorphin and deltorphin glycosylated analogues: synthesis and antinociceptive activity after systemic administration. J. Med. Chem. 1999, 42, 400-404.
25. 4]deltorphin analogs. J. Pharmacol. Exp. Ther. 2000, 293, 151-158.
26. (f) Egleton, R. D.; Mitchell, S. A.; Huber, J. D.; Palian, M. M.; Polt, R.; Davis, T. P. Improved blood-brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation. J. Pharmacol. Exp. Ther. 2001, 299, 967-972.
27. (g) Bilsky, J. E.; Egleton, R. D.; Mitchell, S. A.; Palian, M. M.; Davis, P.; Huber, J. D.; Jones, H.; Yamamura, H. I.; Janders, J.; Davis, T. P.; Porreca, F.; Hruby, V. J.; Polt, R. Enkephalin glycopeptide analogues produce analgesia with reduced dependence liability. J. Med. Chem. 2000, 43, 2586-2590.
28. (h) Palian, M. M.; Boiguslavsky, V. I.; O'Brien, D. F.; Polt, R. Glycopeptide-membrane interactions: glycosyl enkephalin analogues adopt turn conformations by NMR and CD in amphipathic media. J. Am. Chem. Soc. 2003, 125, 5823-5831.
29. Patel, D.; McKinley, B. D.; Davis, T. P.; Porreca, F.; Yamamura, H. I.; Hruby, V. J. Peptide targeting and delivery across the blood-brain barrier utilizing synthetic triglyceride esters: design, synthesis, and bioactivity. Bioconjugate Chem. 1997, 8, 434-441.
30. Gentry, C. L.; Egleton, R. D.; Gillespie, T.; Abbruscato, T. J.; Bechowsi, H. B.; Hruby, V. J.; Davis, T. P. The effect of halogenation on blood-brain barrier permeability of a novel peptide drug. Peptides 1999, 20, 1229-1238.
31. Ogawa, T.; Araki, M.; Miyame, T.; Okayama, T.; Hagiwara, M.; Sakurada, S.; Morikawa, T. Synthesis and antinociceptive activity of orally active opioid peptides: improvement of oral bioavailability by esterification. Chem. Pharm. Bull. 2003, 51, 759-771.
32. Banks, W.; Kastin, A. Passage of peptides across the blood-brain barrier; pathophysiological perspectives. Life Sci. 1996, 59, 1923-1943.
33. Bryant, S. D.; Jinsmaa, Y.; Salvadori, S.; Okada, Y.; Lazarus, L. H. Dmt and opioid peptides: a potent alliance. Biopolymers (Pept. Sci.) 2003, 71, 86-102.
34. Bryant, S. D.; George, C.; Flippen-Anderson, J.; Salvadori, S.; Balboni, G.; Guerrini, R.; Lazarus, L. H. Solid-state structure of analogues containing the Dmt-Tic pharmacophore. J. Med. Chem. 2002, 45, 5506-5513.
35. Okada, Y.; Tsuda, Y.; Fujita, Y.; Yokoi, T.; Sasaki, Y.; Ambo, A.; Konishi, R.; Nagata, M.; Salvadori, S.; Yunden, J.; Bryant, S. D.; Lazarus, L. H. Unique synthetic μ-opioid receptor agonists with central- and systemic-mediated analgesia. J. Med. Chem. 2003, 46, 3201-3209.
36. Capasso, A.; Guerrini, R.; Balboni, G.; Sorrentino, L.; Temussi, P.; Lazarus, L. H.; Bryant, S. D.; Salvadori, S. Dmt-Tic-OH, a highly selective and potent δ-opioid dipeptide receptor antagonist after systemic administration in the mouse. Life Sci. 1996, 59, PL 93-98.
37. Dygos, J. H.; Yonan, E. E.; Scaros, M. G.; Goodmonson, O. J.; Getman, D. P.; Periana, R. A.; Beck, G. R. A convenient asymmetric synthesis of the unnatural amino acid 2,6-dimethyl-L-tyrosine. Synthesis 1992, 8, 741-743.
38. Okada, Y.; Fukumizu, A.; Takahasi, M.; Yamazaki, J.; Yokoi, T.; Tsuda, Y.; Bryant, S. D.; Lazarus, L. H. Amino acids and peptides. LVI. Synthesis of pyrazinone ring-containing opioid mimetics and examination of their opioid receptor binding activity. Tetrahedron 1999, 55, 14391-14406.
39. 1) conotoxin GI analogues in the mouse diaphragm. Int. J. Pept. Protein Res. 1989, 34, 455-462.
40. Honzle, J.; Rudinger, J. Amio-acid and peptides. XXXIII. Nitrosyl chloride and butyl nitrite as reagents in peptide synthesis by azide method: suppression of amide formation. Collect. Czech. Chem. Commun. 1991, 26, 2333-2344.
41. Castro, B.; Dormoy, J.-R.; Evin, G.; Selve, C. Reactifs de couplase peptidique. IV. (1)-L'hexafluorphosphate de benzotriazolul N-oxytrisdimethylamino phosphonium (B.O.P.). Tetrahedron Lett. 1975, 14, 1219-1222.
42. Okada, Y.; Fujisawa, Y.; Morishita, A.; Shiotani, K.; Miyazaki, A.; Fujita, Y.; Li, T.; Tsuda, Y.; Yokoi, T.; Bryant, S. D.; Lazarus, L. H. Immediate deamination from the aminomethyl group attached to 1,2-dihydropyrazin-2-on derivative during catalytic hydrogenation. Tetrahedron. Lett. 2002, 43, 8137-8139.
43. 2,5]enkephalin across the blood-brain barrier involves transcytosis. J. Pharm. Sci. 1999, 88, 392-397.
44. (a) Balboni, G.; Guerrini, R.; Salvadori, S.; Tomatis, R.; Bryant, S. D. ; Bianchi, C.; Attila, M.; Lazarus, L. H. Opioid diketopiperazines: synthesis and activity of a prototypic class of opioid antagonists. Biol. Chem. 1997, 378, 19-29.
45. (b) Bryant, S. D.; Balboni, G.; Guerrini, R.; Salvadori, S.; Tomatis, R. ; Lazarus, L. H. Opioid diketopiperazines: refinement of the δ opioid antagonist pharmacophore. Biol. Chem. 1997, 378, 107-114.
46. Abbruscato, T. J.; Williams, S. A.; Misicka, A.; Lipkowski, A. W.; Hruby, V. J.; Davis, T. P. 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.
47. Sasaki, Y.; Suto, T.; Ambo, A.; Ouchi, H.; Yamamoto, Y. Biological properties of opioid peptides replacing Tyr at position 1 by 2,6-dimethyl-Tyr. Chem. Pharm. Bull. 1999, 47, 1506-1507.
48. 1]DALDA analgesia. Brain Res. 2003, 974, 254-257.
49. Lovekamp, T.; Cooper, P. S.; Hardison, J.; Bryant, S. D.; Guerrini, R.; Balboni, G.; Salvadori, S.; Lazarus, L. H. Inhibition of human multidrug resistance P-glycoprotein 1 by analogues of a potent δ-opioid antagonist. Brain Res. 2001, 902, 131-134.
50. Okada, Y.; Tsukatani, M.; Taguchi, H.; Yokoi, T.; Bryant, S. D.; Lazarus, L. H. Amino acids and peptides. LII. Design and synthesis of opioidmimetics containing pyrazinone ring and examination of their opioid receptor binding activity. Pharm. Chem. Bull. 1998, 46, 1374-1382.
51. (a) Balboni, G.; Salvadori, S.; Guerinni, R.; Negri, L.; Giannini, E.; Yunden, J.; Bryant, S. D.; Lazarus, L. H. New potent δ-opioid agonists based on the Dmt-Tic pharmacophore. J. Med. Chem. 2002, 45, 5556-5563.
52. (b) 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.
53. (a) Shimohigashi, Y.; Costa, T.; Chen, H.-C.; Rodbard, D. Dimeric tetrapeptide enkephalins display extraordinary selectivity for the δ opiate receptor. Nature 1982, 297, 333-335.
54. (b) Shimohigashi, Y.; Costa, T.; Mastuura, S.; Chen, H.-C.; Rodbard, D. Dimeric enkephalins display enhanced affinity and selectivity for the delta opioid receptor. Mol. Pharmacol. 1982, 21, 558-563.
55. (c) Lipkowski, A. W.; Knonecka, A. M.; Sroczynska, I. Double-enkephalins-synthesis, activity on guinea-pig ileum, and analgesic effect. Peptides 1982, 3, 697-700.
56. Lazarus, L. H.; Guglietta, A.; Wilson, W. E.; Irons, B. J.; de Castiglione, R. Dimeric dermorphin analogues as μ-receptor probes on rat brain membranes. Correlation between central μ-receptor potency and suppression of gastric acid secretion. J. Biol. Chem. 1989, 264, 354-362.
57. Kondo, M.; Kodama, H.; Costa, T.; Shimohigashi, Y. Syntheses and biological activities of enkephalin analogues containing cystamine and cysteamine. Int. J. Pept. Protein Res. 1986, 27, 153-159.
58. Egleton, R. D.; Abbruscato, T. J.; Thomas, S. A.; Davis, T. P. Transport of opioid peptides into the central nervous system. J. Pharmaceut. Sci. 1998, 87, 1433-1439.
59. 50) of an enzymatic reaction. Biochem. Pharmacol. 1973, 22, 3099-3108.