Advertisement

Opioids in Preclinical and Clinical Trials

  • Hiroshi NagaseEmail author
  • Hideaki Fujii
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 299)

Abstract

Since 1952, when Gates determined the stereo structure of morphine, numerous groups have focused on discovering a nonnarcotic opioid drug [1]. Although several natural, semisynthetic, and synthetic opioid ligands (alkaloids and peptides) have been developed in clinical studies, very few were nonnarcotic opioid drugs [2]. One of the most important studies in the opioid field appeared in 1976, when Martin and colleagues [3] established types of opioid receptors (these are now classified into μ, δ, and κ types). Later, Portoghese discovered a highly selective μ type opioid receptor antagonist, β-funaltrexamine [4]. This led to the finding that the μ type opioid receptor was correlated to drug dependence [5]. Consequently, δ, and particularly κ, opioid agonists were expected to lead to ideal opioid drugs. Moreover, opioid antagonists were evaluated for the treatment of symptoms related to undesirable opioid system activation. In this chapter, we provide a short survey of opioid ligands in development and describe the discovery of the two most promising drugs, TRK-851 [6] and TRK-820 (nalfurafine hydrochloride) [7].

Graphical Abstract

Keywords

Clinical development Nonnarcotic Opioid drug TRK-820 TRK-851 

Abbreviations

AAW

Acetic acid writhing

ADME

Absorption, distribution, metabolism, and excretion

ADR

Adverse drug reaction

β-FNA

β-Funaltrexamine

BBB

Blood–brain barrier

BNTX

7-Benzylidenenaltrexone

cLog P

Calculated log P

CNS

Central nervous system

CTOP

H-d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2

DAMGO

[d-Ala2, N-Me-Phe4, Gly-ol5]enkephalin

DPDPE

[d-Pen2, d-Pen5]enkephalin

DSLET

Tyr-d-Ser-Gly-Phe-Leu-Thr

GPI

Guinea pig ileum

HPLC

High-performance liquid chromatography

i.c.

Intracisternal

i.d.

Intradermal

i.p.

Intraperitoneal

i.t.

Intrathecal

MVD

Mouse vas deferens

nor-BNI

nor-Binaltorphimine

NTI

Naltrindole

PBS

Phosphate-buffered saline

p.o.

Peroral

SAR

Structure–activity relationship

s.c.

Subcutaneous

S.E.M.

Standard error of the mean

TF

Tail flick

VAS

Visual analog scale

References

  1. 1.
    Gates M, Tschudi G (1952) J Am Chem Soc 74:1109CrossRefGoogle Scholar
  2. 2.
    Casy AF, Parfitt RT (1986) Opioid analgesics, chemistry and receptors. Plenum, New YorkGoogle Scholar
  3. 3.
    Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (1976) J Pharmacol Exp Ther 197:517Google Scholar
  4. 4.
    Takemori AE, Larson DL, Portoghese PS (1981) Eur J Pharmacol 70:445CrossRefGoogle Scholar
  5. 5.
    DeLander GE, Portoghese PS, Takemori AE (1984) J Pharmacol Exp Ther 231:91Google Scholar
  6. 6.
    Sakami S, Kawai K, Maeda M, Aoki T, Fujii H, Ohno H, Ito T, Saitoh A, Nakao K, Izumimoto N, Matsuura H, Endo T, Ueno S, Natsume K, Nagase H (2008) Bioorg Med Chem 16:7956CrossRefGoogle Scholar
  7. 7.
    Nagase H, Hayakawa J, Kawamura K, Kawai K, Takezawa Y, Matsuura H, Tajima C, Endo T (1988) Chem Pharm Bull 46:366Google Scholar
  8. 8.
    Turgeon J, Gröning R, Sathyan G, Thipphawong J, Richarz U (2010) Expert Opin Drug Deliv 7:137CrossRefGoogle Scholar
  9. 9.
    Matsumoto AK (2007) Expert Opin Pharmacother 8:1515CrossRefGoogle Scholar
  10. 10.
    Nelson L, Schwaner R (2009) J Med Toxicol 5:230CrossRefGoogle Scholar
  11. 11.
    Vadivelu N, Hines RL (2008) Clin Interv Aging 3:421Google Scholar
  12. 12.
    Stauffer J, Setnik B, Sokolowska M, Romach M, Johnson F, Sellers E (2009) Clin Drug Investig 29:777CrossRefGoogle Scholar
  13. 13.
    Diego L, Atayee R, Helmons P, von Gunten CF (2009) Expert Rev Gastroenterol Hepatol 3:473CrossRefGoogle Scholar
  14. 14.
    Bream-Rouwenhorst HR, Cantrell MA (2009) Am J Health Syst Pharm 66:1267CrossRefGoogle Scholar
  15. 15.
    Calderon SN, Coop A (2004) Curr Pharm Des 10:733CrossRefGoogle Scholar
  16. 16.
    Gengo PJ, Pettit HO, O'Neill SJ, Wei K, McNutt R, Bishop MJ, Chang KJ (2003) J Pharmacol Exp Ther 307:1221CrossRefGoogle Scholar
  17. 17.
    Le Bourdonnec B, Windh RT, Ajello CW, Leister LK, Gu M, Chu GH, Tuthill PA, Barker WM, Koblish M, Wiant DD, Graczyk TM, Belanger S, Cassel JA, Feschenko MS, Brogdon BL, Smith SA, Christ DD, Derelanko MJ, Kutz S, Little PJ, DeHaven RN, DeHaven-Hudkins DL, Dolle RE (2008) J Med Chem 51:5893CrossRefGoogle Scholar
  18. 18.
    Le Bourdonnec B, Windh RT, Leister LK, Zhou QJ, Ajello CW, Gu M, Chu GH, Tuthill PA, Barker WM, Koblish M, Wiant DD, Graczyk TM, Belanger S, Cassel JA, Feschenko MS, Brogdon BL, Smith SA, Derelanko MJ, Kutz S, Little PJ, DeHaven RN, DeHaven-Hudkins DL, Dolle RE (2009) J Med Chem 52:5685CrossRefGoogle Scholar
  19. 19.
    Katsura Y, Zhang X, Homma K, Rice KC, Calderon SN, Rothman RB, Yamamura HI, Davis P, Flippen-Anderson JL, Xu H, Becketts K, Foltz EJ, Porreca F (1997) J Med Chem 40:2936CrossRefGoogle Scholar
  20. 20.
    Nagase H, Kawai K, Hayakawa J, Wakita H, Mizusuna A, Matsuura H, Tajima C, Takezawa Y, Endoh T (1998) Chem Pharm Bull 46:1695Google Scholar
  21. 21.
    Nagase H, Yajima Y, Fujii H, Kawamura K, Narita M, Kamei J, Suzuki T (2001) Life Sci 68:2227CrossRefGoogle Scholar
  22. 22.
    Portoghese PS, Takemori AE (1994) USP 5,352,680Google Scholar
  23. 23.
    Suzuki T, Tsuji M, Mori T, Misawa M, Nagase H (1995) Life Sci 57:PL247CrossRefGoogle Scholar
  24. 24.
    Suzuki T, Tsuji M, Mori T, Misawa M, Nagase H (1997) Pharmacol Biochem Behav 57:293CrossRefGoogle Scholar
  25. 25.
    Arakawa K, Akami T, Okamoto M, Akioka K, Nakai I, Oka T, Nagase H (1993) Transplant Proc 25(1 Pt 1):738Google Scholar
  26. 26.
    Gavériaux-Ruff C, Filliol D, Simonin F, Matthes HW, Kieffer BL (2001) J Pharmacol Exp Ther 298:1193Google Scholar
  27. 27.
    Piercey MF, Lahti RA, Schroeder LA, Einspahr FJ, Barsuhn C (1982) Life Sci 31:1197CrossRefGoogle Scholar
  28. 28.
    Kawai K, Hayakawa J, Miyamoto T, Imamura Y, Yamane S, Wakita H, Fujii H, Kawamura K, Matsuura H, Izumimoto N, Kobayashi R, Endo T, Nagase H (2008) Bioorg Med Chem 16:9188CrossRefGoogle Scholar
  29. 29.
    Costello GF, Main BG, Barlow JJ, Carroll JA, Shaw JS (1988) Eur J Pharmacol 151:475CrossRefGoogle Scholar
  30. 30.
    Halfpenny PR, Horwell DC, Hughes J, Hunter JC, Rees DC (1990) J Med Chem 33:286CrossRefGoogle Scholar
  31. 31.
    Chang KF, Chang AB (2002) Pulm Pharmacol Ther 15:335CrossRefGoogle Scholar
  32. 32.
    Bolser DC (2006) Respir Physiol Neurobiol 152:349CrossRefGoogle Scholar
  33. 33.
    Kamei J, Tanihara H, Kasuya Y (1990) Eur J Pharmacol 187:281CrossRefGoogle Scholar
  34. 34.
    Kamei J, Tanihara H, Kasuya Y (1991) Eur J Pharmacol 203:153CrossRefGoogle Scholar
  35. 35.
    Kamei J, Tanihara H, Kasuya Y (1992) Chem Pathol Pharmacol 76:375Google Scholar
  36. 36.
    Kamei J, Iwamoto Y, Suzuki T, Misawa M, Nagase H, Kasuya Y (1993) Eur J Pharmacol 249:161CrossRefGoogle Scholar
  37. 37.
    Hitchcock SA, Pennington LD (2006) J Med Chem 49:7559CrossRefGoogle Scholar
  38. 38.
    Kerns E, Di L (2008) Drug-like properties: concepts, structure design and methods from ADME to toxicity optimization. Academic, LondonGoogle Scholar
  39. 39.
    Sakami S, Maeda M, Kawai K, Aoki T, Kawamura K, Fujii H, Hasebe K, Nakajima M, Endo T, Ueno S, Ito T, Kamei J, Nagase H (2008) J Med Chem 51:4404CrossRefGoogle Scholar
  40. 40.
    Nagase H, Kawai K, Kawamura K, Hayakawa J, Endo T (1993) WO 93/15081Google Scholar
  41. 41.
    Portoghese PS, Lipkowski AW, Takemori AE (1987) J Med Chem 30:238CrossRefGoogle Scholar
  42. 42.
    Portoghese PS, Sultana M, Nagase H, Takemori AE (1988) J Med Chem 31:281CrossRefGoogle Scholar
  43. 43.
    Nogrady T (1985) Medicinal chemistry, a biochemical approach. Oxford University Press, New YorkGoogle Scholar
  44. 44.
    Portoghese PS, Nagase H, Takemori AE (1988) J Med Chem 31:1344CrossRefGoogle Scholar
  45. 45.
    Lin CE, Takemori AE, Portoghese PS (1993) J Med Chem 36:2412CrossRefGoogle Scholar
  46. 46.
    Shook JE, Pelton JT, Wire WS, Hirning LD, Hruby VJ, Burks TF (1987) J Pharmacol Exp Ther 240:772Google Scholar
  47. 47.
    Endo T, Matsuura H, Tajima A, Izumimoto N, Tajima C, Suzuki T, Saitoh A, Suzuki T, Narita M, Tseng L, Nagase H (1999) Life Sci 65:1685CrossRefGoogle Scholar
  48. 48.
    Kanematsu K (1998) Yakugaku Zasshi 118:1Google Scholar
  49. 49.
    Katsumata S, Ienaga Y, Minami M, Nakagawa T, Kanematsu K, Satoh M (1996) Eur J Pharmacol 312:349CrossRefGoogle Scholar
  50. 50.
    Hosoki R, Niizawa S, Koike K, Sagara T, Kanematsu K, Takayanagi I (1996) Arch Int Pharmacodyn Ther 331:136Google Scholar
  51. 51.
    Togashi Y, Umeuchi H, Okano K, Ando N, Yoshizawa Y, Honda T, Kawamura K, Endoh T, Utsumi J, Kamei J, Tanaka T, Nagase H (2002) Eur J Pharmacol 435:259CrossRefGoogle Scholar
  52. 52.
    Umeuchi H, Togashi Y, Honda T, Nakao K, Okano K, Tanaka T, Nagase H (2003) Eur J Pharmacol 477:29CrossRefGoogle Scholar
  53. 53.
    Wakasa Y, Fujiwara A, Umeuchi H, Endoh T, Okano K, Tanaka T, Nagase H (2004) Life Sci 75:2947CrossRefGoogle Scholar
  54. 54.
    Utsumi J, Togashi Y, Umeuchi H, Okano K, Tanaka T, Nagase H (2004) In: Yosipovitch G, Greaves MW, Fleischer AB Jr, McGlone F (eds) Itch. Basic mechanisms and therapy. Marcel Dekker, New York, p 107Google Scholar
  55. 55.
    Inan S, Cowan A (2004) Eur J Pharmacol 502:233CrossRefGoogle Scholar
  56. 56.
    Wang Y, Tang K, Inan S, Siebert D, Holzgrabe U, Lee DYW, Huang P, Li J-G, Cowan A, Liu-Chen L-Y (2005) J Pharmacol Exp Ther 312:220CrossRefGoogle Scholar
  57. 57.
    Nakao K, Mochizuki H (2009) Drugs Today 45:323CrossRefGoogle Scholar
  58. 58.
    Ko MC, Husbands SM (2009) J Pharmacol Exp Ther 328:193CrossRefGoogle Scholar
  59. 59.
    Cousins MJ, Mather LE (1984) Anesthesiology 61:276CrossRefGoogle Scholar
  60. 60.
    Ballantyne JC, Loach AB, Carr DB (1988) Pain 33:149CrossRefGoogle Scholar
  61. 61.
    Kuraishi Y, Nagasawa T, Hayashi K, Satoh M (1995) Eur J Pharmacol 275:229CrossRefGoogle Scholar
  62. 62.
    Andoh T, Nagasawa T, Satoh M, Kuraishi Y (1998) J Pharmacol Exp Ther 286:1140Google Scholar
  63. 63.
    Tohda C, Yamaguchi T, Kuraishi Y (1997) Jpn J Pharmacol 74:77CrossRefGoogle Scholar
  64. 64.
    Umeuchi H, Kawashima Y, Aoki CA, Kurokawa T, Nakao K, Itoh M, Kikuchi K, Kato T, Okano K, Gershwin ME, Miyakawa H (2005) Eur J Pharmacol 518:133CrossRefGoogle Scholar
  65. 65.
    Inan S, Cowan A (2006) Pharmacol Biochem Behav 85:39CrossRefGoogle Scholar
  66. 66.
    Wikström B, Gellert R, Ladefoged SD, Danda Y, Akai M, Ide K, Ogasawara M, Kawashima Y, Ueno K, Mori A, Ueno Y (2005) J Am Soc Nephrol 16:3742CrossRefGoogle Scholar
  67. 67.
    Kumagai H, Ebata T, Takamori K, Muramatsu T, Nakamoto H, Suzuki H (2009) Nephrol Dial Transplant (in press). doi: 10.1093/ndt/gfp588
  68. 68.
    Kumagai H, Ebata T, Suzuki H, Takamori K (2008) 10th Souyaku vision symposium, Tokyo, 18–19 Dec 2008, The Pharmaceutical Society of Japan, p 24Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.School of PharmacyKitasato UniversityTokyoJapan

Personalised recommendations