Skip to main content

Synthesis of 14-Alkoxymorphinan Derivatives and Their Pharmacological Actions

  • Chapter
  • First Online:
Chemistry of Opioids

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 299))

Abstract

Among opioids, morphinans play an important role as therapeutically valuable drugs. They include pain relieving agents such as naturally occurring alkaloids (e.g. morphine, codeine), semisynthetic derivatives (e.g. oxycodone, oxymorphone, buprenorphine), and synthetic analogs (e.g. levorphanol). Currently used opioid analgesics also share a number of severe side effects, limiting their clinical usefulness. The antagonist morphinans, naloxone and naltrexone are used to treat opioid overdose, opioid dependence, and alcoholism. All these opioid drugs produce their biological actions through three receptor types, µ, δ, and κ, belonging to the G-protein-coupled receptor family. Considerable effort has been put forward to understand the appropriate use of opioid analgesics, while medicinal chemistry and opioid pharmacology have been continuously engaged in the search for safer, more efficacious and nonaddicting opioid compounds, with the final goal to reduce complications and to improve patient compliance. Toward this goal, recent advances in chemistry, ligand-based structure activity relationships and pharmacology of 14-alkoxymorphinans are reviewed in this chapter. Current developments of different structural patterns of 14-alkoxymorphinans as research tools and their potential therapeutic opportunities are also summarized.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

[35S]GTPγS:

Guanosine-5′-O-(3-[35S]thio)-triphosphate

AD50 :

Analgesic dose necessary to elicit a 50% effect

BBB:

Blood–brain barrier

CBE:

Colonic bead expulsion test

CHO:

Chinese hamster ovary

CNS:

Central nervous system

DMF:

N,N-dimethylformamide

ED50 :

Effective dose necessary to elicit a 50% effect

GPI:

Guinea pig ileum bioassay

HP:

Hot-plate test

IC50 :

Concentration necessary to produce a 50% effect

IL-2:

Interleukin-2

K i :

Inhibition constant

MeOH:

Methanol

MLR:

Mixed lymphocyte reaction

MVD:

Mouse vas deferens bioassay

NaH:

Sodium hydride

NTB:

Naltriben

NTI:

Naltrindole

PBMC:

Peripheral blood mononuclear cells

PPOM:

14-Phenylpropoxymetopon

PPQ:

Paraphenylquinone writhing test

RVD:

Rat vas deferens bioassay

SAR:

Structure–activity relationship

s.c.:

Subcutaneous

TF:

Tail-flick test

TosMIC:

Tosylmethylisocyanid

References

  1. Evans CJ (2004) Secrets of opium poppy revealed. Neuropharmacology 47:293–299

    CAS  Google Scholar 

  2. Kieffer BL, Evans CJ (2009) Opioid receptors: from binding sites to visible molecules in vivo. Neuropharmacology 56:205–212

    CAS  Google Scholar 

  3. Mansour A, Fox CA, Akil H, Watson SJ (1995) Opioid-receptor mRNA expression in the rat CNS: Anatomical and functional implications. Trends Neurosci 18:22–29

    CAS  Google Scholar 

  4. McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ (2001) Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 62:111–123

    CAS  Google Scholar 

  5. Stein C (2003) Opioid receptors on peripheral sensory neurons. Adv Exp Med Biol 521:69–76

    CAS  Google Scholar 

  6. Holzer P (2009) Opioid receptors in the gastrointestinal tract. Regul Pept 155:11–17

    CAS  Google Scholar 

  7. Kieffer BL, Gaveriaux-Ruff C (2002) Exploring the opioid system by gene knockout. Prog Neurobiol 66:285–306

    CAS  Google Scholar 

  8. Bodnar RJ (2009) Endogenous opiates and behavior: 2008. Peptides 30:2432–2479

    CAS  Google Scholar 

  9. Zimmerman DM, Leander JD (1990) Selective opioid receptor agonists and antagonists: research tools and potential therapeutic agents. J Med Chem 33:895–902

    CAS  Google Scholar 

  10. Takemori AE, Portoghese PS (1992) Selective naltrexone-derived opioid receptors antagonists. Annu Rev Pharmacol Toxicol 32:239–269

    CAS  Google Scholar 

  11. Borsodi A, Toth G (1995) Characterization of opioid receptor types and subtypes with new ligands. Ann NY Acad Sci 757:339–352

    CAS  Google Scholar 

  12. Schmidhammer H (1998) Opioid receptor antagonists. In: Ellis GP, Luscombe DK, Oxford AW (eds) Prog Med Chem 35:83–132

    Google Scholar 

  13. Schiller PW, Weltrowska G, Berezowska I, Nguyen TM, Wilkes BC, Lemieux C, Chung NN (1999) The TIPP opioid peptide family: development of δ antagonists, δ agonists, and mixed µ agonist/δ antagonists. Biopolymers 51:411–425

    CAS  Google Scholar 

  14. DeHaven-Hudkins DL, Dolle RE (2004) Peripherally restricted agonists as novel analgesic agents. Curr Pharm Design 10:743–757

    CAS  Google Scholar 

  15. Eguchi M (2004) Recent advances in selective opioid receptor agonists and antagonists. Med Res Rev 24:182–212

    CAS  Google Scholar 

  16. Metcalf MD, Coop A (2005) Kappa opioid antagonists: past successes and future prospects. AAPS J 7:E704–E722

    CAS  Google Scholar 

  17. Schiller PW (2005) Opioid peptide-derived analgesics. AAPS J 7:E560–E565

    CAS  Google Scholar 

  18. Goodman AJ, Le Bourdonnec B, Dolle RE (2007) Mu opioid receptor antagonists: recent developments. Chem Med Chem 2:1552–1557

    CAS  Google Scholar 

  19. Fürst S, Hosztafi S (2008) The chemical and pharmacological importance of morphine analogues. Acta Physiol Hung 95:3–44

    Google Scholar 

  20. Trescot AM, Datta S, Lee M, Hansen H (2008) Opioid pharmacology. Pain Physician 11:S133–S153

    Google Scholar 

  21. Nicholson B (2009) Benefits of extended-release opioid analgesic formulations in the treatment of chronic pain. Pain Pract 9:71–81

    Google Scholar 

  22. Blumberg H, Dayton HB, Wolf PS (1966) Counteraction of narcotic antagonist analgesics by the narcotic antagonist naloxone. Proc Soc Exp Biol Med 123:755–758

    CAS  Google Scholar 

  23. Resnick RB, Volavka J, Freedman AM, Thomas M (1974) Studies of EN-1639A (naltrexone): a new narcotic antagonist. Am J Psychiatry 131:646–650

    CAS  Google Scholar 

  24. O'Malley SS (1996) Opioid antagonists in the treatment of alcohol dependence: clinical efficacy and prevention of relapse. Alcohol Alcohol Suppl 1:77–81

    Google Scholar 

  25. Morris PL, Hopwood M, Whelan G, Gardiner J, Drummond E (2001) Naltrexone for alcohol dependence: a randomized controlled trial. Addiction 96:1565–1573

    CAS  Google Scholar 

  26. Brown DR, Goldberg LI (1985) The use of quaternary narcotic antagonists in opiate research. Neuropharmacology 24:181–191

    CAS  Google Scholar 

  27. Viscusi ER, Gan TJ, Leslie JB, Foss JF, Talon MD, Du W, Owens G (2009) Peripherally acting µ-opioid receptor antagonists and postoperative ileus: mechanisms of action and clinical applicability. Anesth Analg 108:1811–1822

    CAS  Google Scholar 

  28. Nagase H, Hayakawa J, Kawamura K, Kawai K, Takezawa Y, Matsuura H, Tajima C, Endo T (1998) Discovery of a structurally novel opioid kappa-agonist derived from 4, 5-epoxymorphinan. Chem Pharm Bull 46:366–369

    CAS  Google Scholar 

  29. Nakao K, Mochizuki H (2009) Nalfurafine hydrochloride: a new drug for the treatment of uremic pruritus in hemodialysis patients. Drugs Today 45:323–329

    Google Scholar 

  30. Coop A, Rice KC (2000) Role of δ-opioid receptors in biological processes. Drug News Perspect 13:481–487

    CAS  Google Scholar 

  31. Sadée W, Wang D, Bilsky EJ (2005) Basal opioid receptor activity, neutral antagonists, and therapeutic opportunities. Life Sci 76:1427–1437

    Google Scholar 

  32. Cunningham CW, Coop A (2006) Therapeutic applications of opioid antagonists. Chem Today 24:54–57

    CAS  Google Scholar 

  33. Schmidhammer H, Burkard WP, Eggstein-Aeppli L, Smith CFC (1989) Synthesis and biological evaluation of 14-alkoxymorphinans. 2. (-)-N-(cyclopropylmethyl)-4, 14-dimethoxymorphinan-6-one, a selective µ opioid receptor antagonist. J Med Chem 32:418–421

    CAS  Google Scholar 

  34. Portoghese PS, Sultana M, Takemori AE (1988) Naltrindole, a highly selective and potent non-peptide δ-opioid receptor antagonist. Eur J Pharmacol 146:185–186

    CAS  Google Scholar 

  35. Portoghese PS, Lipkowski AW, Takemori AE (1987) Binaltorphimine and nor-binaltorphimine, potent and selective κ-opioid receptor antagonists. Life Sci 40:1287–1292

    CAS  Google Scholar 

  36. Heinisch G, Klintz V, Viehböck F (1971) Methanolysis of 14-bromocodeinone dimethyl acetale. Monatsh Chem 102:530–539

    CAS  Google Scholar 

  37. Razdan RK, Ghosh AC (1980) US Patent No 4,232,028

    Google Scholar 

  38. Kobylecki RJ, Carling RW, Lord JAH, Smith CFC, Lane AC (1982) Common anionic receptor site hypothesis: its relevance to the antagonist action of naloxone. J Med Chem 25:116–120

    CAS  Google Scholar 

  39. Razdan RK, Ghosh AC (1980) UK Patent No 2,045,758

    Google Scholar 

  40. Ghosh AC, Razdan RK (1982) US Patent No 4,362,733

    Google Scholar 

  41. Schmidhammer H, Aeppli L, Atwell L, Fritsch F, Jacobson AE, Nebuchla M, Sperk G (1984) Synthesis and biological evaluation of 14-alkoxymorphinans. 1. Highly potent opioid agonists in the series of (–)-14-methoxy-N-methylmorphinan-6-ones. J Med Chem 27:1575–1579

    CAS  Google Scholar 

  42. Schmidhammer H, Jennewein HK, Krassnig R, Traynor JR, Patel D, Bell K, Froschauer G, Mattersberger K, Jachs-Ewinger C, Jura P, Fraser GL, Kalinin VN (1995) Synthesis and biological evaluation of 14-alkoxymorphinans. 11. 3-Hydroxycyprodime and analogues: opioid antagonist profile in comparison to cyprodime. J Med Chem 38:3071–3077

    CAS  Google Scholar 

  43. Schütz J, Dersch CM, Horel R, Spetea M, Koch M, Meditz R, Greiner E, Rothman RB, Schmidhammer H (2002) Synthesis and biological evaluation of 14-alkoxymorphinans. 17. Highly δ opioid receptor selective 14-alkoxy-substituted indolo- and benzofuromorphinans. J Med Chem 45:5378–5383

    Google Scholar 

  44. Greiner E, Spetea M, Krassnig R, Schüllner F, Aceto M, Harris LS, Traynor JR, Woods JH, Coop A, Schmidhammer H (2003) Synthesis and biological evaluation of 14-alkoxymorphinans. 18. N-Substituted 14-phenylpropoxymorphinan-6-ones with unanticipated agonist properties: extending the scope of common structure-activity relationships. J Med Chem 46:1758–1763

    CAS  Google Scholar 

  45. Schütz J, Spetea M, Koch M, Aceto MD, Harris LS, Coop A, Schmidhammer H (2003) Synthesis and biological evaluation of 14-alkoxymorphinans. 20. 14-Phenylpropoxymetopon: an extremely powerful analgesic. J Med Chem 46:4182–4187

    Google Scholar 

  46. Cami-Kobeci G, Neal AP, Bradbury FA, Purington LC, Aceto MD, Harris LS, Lewis JW, Traynor JR, Husbands SM (2009) Mixed κ/µ opioid receptor agonists: the 6β-naltrexamines. J Med Chem 52:1546–1552

    CAS  Google Scholar 

  47. Lattanzi R, Spetea M, Schüllner F, Rief SB, Krassnig R, Negri L, Schmidhammer H (2005) Synthesis and biological evaluation of 14-alkoxymorphinans. 22. Influence of the 14-alkoxy group and the substitution in position 5 in 14-alkoxymorphinan-6-ones on in vitro and in vivo activities. J Med Chem 48:3372–3378

    CAS  Google Scholar 

  48. Schüllner F, Meditz R, Krassnig R, Morandell G, Kalinin VN, Sandler E, Spetea M, White A, Schmidhammer H, Berzetei-Gurske IP (2003) Synthesis and biological evaluation of 14-alkoxymorphinans. 19. Effect of 14-O-benzylation on the opioid receptor affinity and antagonist potency of naltrexone. Helv Chim Acta 86:2335–2341

    Google Scholar 

  49. Schmidhammer H, Daurer D, Wieser M, Monory K, Borsodi A, Elliott J, Traynor JR (1997) Synthesis and biological evaluation of 14-alkoxymorphinans. 14. 14-Ethoxy-5-methyl substituted indolomorphinans with δ opioid receptor selectivity. Bioorg Med Chem Lett 7:151–156

    CAS  Google Scholar 

  50. Biyashev D, Monory K, Benyhe S, Schütz J, Koch M, Schmidhammer H, Borsodi A (2001) Novel delta-opioid-receptor-selective ligands in the 14-alkoxy-substituted indolo- and benzofuromorphinan series. Helv Chim Acta 84:2015–2021

    CAS  Google Scholar 

  51. Portoghese PS, Sultana M, Nagase H, Takemori AE (1988) Application of the message-address concept in the design of highly potent and selective non-peptide δ opioid receptor antagonists. J Med Chem 31:281–282

    CAS  Google Scholar 

  52. Portoghese PS, Nagase H, Maloney Huss KE, Lin C-E, Takemori AE (1991) Role of spacer and address components in peptidomimetic δ opioid receptor antagonists related to naltrindole. J Med Chem 34:1715–1720

    CAS  Google Scholar 

  53. Schmidhammer H, Schwarz P, Wei Z-Y (1998) A novel and efficient synthesis of 14-alkoxy-substituted indolo- and benzofuromorphinans in the series of selective δ opioid receptor antagonists. Helv Chim Acta 81:1215–1222

    CAS  Google Scholar 

  54. Pasternak GW, Hahn EF (1980) Long-acting opiate agonists and antagonists: 14-hydroxydihydromorphinone hydrazones. J Med Chem 23:674–676

    CAS  Google Scholar 

  55. Varga E, Toth G, Benyhe S, Hosztafi S, Borsodi A (1987) Synthesis and binding of 3H-oxymorphazone to rat brain membranes. Life Sci 40:1579–1588

    CAS  Google Scholar 

  56. Krizsan D, Varga E, Hosztafi S, Benyhe S, Szucs M, Borsodi A (1991) Irreversible blockade of the high and low affinity (3H)naloxone binding sites by C-6 derivatives of morphinan-6-ones. Life Sci 48:439–451

    CAS  Google Scholar 

  57. Fürst Z, Borsodi A, Friedmann T, Hosztafi S (1992) 6-Substituted oxycodone derivatives have strong antinociceptive effects and block irreversibly the low affinity [3H]-naloxone binding sites in rat brain. Pharm Res 25:31–32

    Google Scholar 

  58. Fürst S, Hosztafi S, Friedmann T (1995) Structure-activity relationships of synthetic and semisynthetic opioid agonists and antagonists. Curr Med Chem 1:423–440

    Google Scholar 

  59. Monory K, Greiner E, Sartania N, Sallai L, Pouille Y, Schmidhammer H, Hanoune J, Borsodi A (1999) Opioid binding profiles of new hydrazone, oxime, carbazone and semicarbazone derivatives of 14-alkoxymorphinans. Life Sci 64:2011–2020

    CAS  Google Scholar 

  60. Gergely A, Gyimesi-Forras K, Horvath P, Hosztafi S, Kökösi J, Nagy PI, Szasz G, Szentesi A (2004) 6-Oxo-morphinane oximes: pharmacology, chemistry and analytical application. Curr Med Chem 11:2555–2564

    CAS  Google Scholar 

  61. Oldenziel OH, van Leusen D, van Leusen AM (1977) Chemistry of solfonylmethyl isocyanides. 13. A general one-step synthesis of nitriles from ketones using tosylmethyl isocyanide. Introduction of a one-carbon unit. J Org Chem 42:3114–3118

    CAS  Google Scholar 

  62. Greiner E, Schottenberger H, Wurst K, Schmidhammer H (2001) Novel class of morphinans with acrylonitrile incorporated substructures as key intermediates for non-oxygen-bridged opioid ligands. J Am Chem Soc 123:3840–3841

    CAS  Google Scholar 

  63. Schütz J, Windisch P, Kristeva E, Wurst K, Ongania K-H, Horvath UIE, Schottenberger H, Laus G, Schmidhammer H (2005) Mechanistic diversity of the van Leusen reaction applied to 6-ketomorphinans and synthetic potential of the resulting acrylonitrile substructures. J Org Chem 70:5323–5326

    Google Scholar 

  64. Botros S, Lipkowski AW, Larson DL, Stark AP, Takemori AE, Portoghese PS (1989) Opioid agonist and antagonist activities of peripherally selective derivatives of naltrexamine and oxymorphamine. J Med Chem 32:2068–2071

    CAS  Google Scholar 

  65. Portoghese PS, Farouz-Grant F, Sultana M, Takemori AE (1995) 7′-Substituted amino acid conjugates of naltrindole. Hydrophilic groups as determinants of selective antagonism of δ1 opioid receptor-mediated antinociception in mice. J Med Chem 38:402–407

    CAS  Google Scholar 

  66. Schütz J, Brandt W, Spetea M, Wurst K, Wunder G, Schmidhammer H (2003) Synthesis of 6-amino acid substituted derivatives of the highly potent analgesic 14-O-methyloxymorphone. Helv Chim Acta 86:2142–2148

    Google Scholar 

  67. Riba P, Friedmann T, Király KP, Al-Khrasani M, Sobor M, Asim MF, Spetea M, Schmidhammer H, Fürst S (2010) Novel approach to demonstrate high efficacy of micro opioids in the rat vas deferens: a simple model of predictive value. Brain Res Bull 81:178–184

    CAS  Google Scholar 

  68. Fürst S, Riba P, Friedmann T, Tímar J, Al-Khrasani M, Obara I, Makuch W, Spetea M, Schütz J, Przewlocki R, Przewlocka B, Schmidhammer H (2005) Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat. J Pharmacol Exp Ther 312:609–618

    Google Scholar 

  69. Schmidhammer H, Schratz A, Mitterdorfer J (1990) Synthesis and biological evaluation of 14-alkoxymorphinans. 8. 14-Methoxymetopon, an extremely potent opioid agonist. Helv Chim Acta 73:1784–1787

    CAS  Google Scholar 

  70. Freye E, Schmidhammer H, Latasch L (2000) 14-Methoxymetopon, a potent opioid, induces no respiratory depression, less sedation, and less bradycardia than sufentanil in the dog. Anesth Analg 90:1359–1364

    CAS  Google Scholar 

  71. Zernig G, Saria A, Krassnig R, Schmidhammer H (2000) Signal transduction efficacy of the highly potent µ-opioid agonist 14-methoxymetopon. Life Sci 66:1871–1877

    CAS  Google Scholar 

  72. Urigüen L, Fernandez B, Romero EM, De Pedro N, Delgado MJ, Guaza C, Schmidhammer H, Viveros MP (2002) Effects of 14-methoxymetopon, a potent opioid agonist, on the responses to the tail electric stimulation test and plus-maze activity in male rats: neuroendocrine correlates. Brain Res Bull 57:661–666

    Google Scholar 

  73. King MA, Su W, Nielan C, Chang AH, Schütz J, Schmidhammer H, Pasternak GW (2003) 14-Methoxymetopon, a very potent µ-opioid analgesic with an unusual pharmacological profile. Eur J Pharmacol 459:203–209

    CAS  Google Scholar 

  74. Spetea M, Tóth F, Schütz J, Ötvös F, Tóth G, Benyhe S, Borsodi A, Schmidhammer H (2003) Binding characteristics of [3H]14-methoxymetopon, a high affinity µ-opioid receptor agonist. Eur J Neurosci 18:290–295

    Google Scholar 

  75. Bileviciute-Ljungar I, Spetea M, Guo Y, Schütz J, Windisch P, Schmidhammer H (2006) Peripherally mediated antinociception of the µ-opioid receptor agonist 2-[(4, 5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-yl)amino]acetic acid (HS-731) after subcutaneous and oral administration in rats with carrageenan-induced hindpaw inflammation. J Pharmacol Exp Ther 317:220–227

    CAS  Google Scholar 

  76. Király KP, Riba P, D'Addario C, Di Benedetto M, Landuzzi D, Candelotti S, Romualdi P, Fürst S (2006) Alterations in prodynorphin gene expression and dynorphin levels in different brain regions after chronic administration of 14-methoxymetopon and oxycodone-6-oxime. Brain Res Bull 70:233–239

    Google Scholar 

  77. Mahurter L, Garceau C, Marino J, Schmidhammer H, Toth G, Pasternak GW (2006) Separation of binding affinity and intrinsic activity of the potent µ-opioid 14-methoxymetopon. J Pharmacol Exp Ther 319:247–253

    CAS  Google Scholar 

  78. Sabino V, Cottone P, Steardo L, Schmidhammer H, Zorrilla EP (2007) 14-Methoxymetopon, a highly potent µ opioid agonist, biphasically affects ethanol intake in sardinian alcohol-preferring rats. Psychopharmacology 192:537–546

    CAS  Google Scholar 

  79. Fürst S, Búzás B, Friedmann T, Schmidhammer H, Borsodi A (1993) Highly potent novel opioid receptor agonist in the 14-alkoxymetopon series. Eur J Pharmacol 236:209–215

    Google Scholar 

  80. Stegmann GF (1999) Etorphine-halothane anaesthesia in two five-year-old African elephants (Loxodonta africana). J S Afr Vet Assoc 70:164–166

    CAS  Google Scholar 

  81. Sterken J, Troubleyn J, Gasthuys F, Maes V, Diltoer M, Verborgh C (2004) Intentional overdose of large animal immobilon. Eur J Emerg Med 11:298–301

    Google Scholar 

  82. Feinberg AP, Creese I, Snyder SH (1976) The opiate receptor: a model explaining structure-activity relationships of opiate agonists ad antagonists. Proc Natl Acad Sci USA 73:4215–4219

    CAS  Google Scholar 

  83. Casy AF, Parfitt RT (1986) Opioid analgesics: chemistry and receptors. Plenum, New York

    Google Scholar 

  84. Spetea M, Schüllner F, Moisa RC, Berzetei-Gurske IP, Schraml B, Dörfler C, Aceto MD, Harris LS, Coop A, Schmidhammer H (2004) Synthesis and biological evaluation of 14-alkoxymorphinans. 21. Novel 4-alkoxy and 14-phenylpropoxy derivatives of the µ opioid receptor antagonist cyprodime. J Med Chem 47:3242–3247

    CAS  Google Scholar 

  85. Spetea M, Greiner E, Aceto MD, Harris LS, Coop A, Schmidhammer H (2005) Effect of a 6-cyano substituent in 14-oxygenated N-methylmorphinans on opioid receptor binding and antinociceptive potency. J Med Chem 48:5052–5055

    CAS  Google Scholar 

  86. Stein C, Clark JD, Oh U, Vasko MR, Wilcox GL, Overland AC, Vanderah TW, Spencer RH (2009) Peripheral mechanisms of pain and analgesia. Brain Res Rev 60:90–113

    CAS  Google Scholar 

  87. Stein C, Schäfer M, Machelska H (2003) Attaching pain at its source: new perspectives on opioids. Nat Med 9:1003–1008

    CAS  Google Scholar 

  88. Walker JS (2003) Anti-inflammatory effects of opioids. Adv Exp Med Biol 521:148–160

    CAS  Google Scholar 

  89. Smith HS (2008) Peripherally-acting opioids. Pain Physician 11:S121–S132

    Google Scholar 

  90. Iorio MA, Frigni V (1984) Narcotic agonist/antagonist properties of quaternary diastereoisomers derived from oxymorphone and naloxone. Eur J Med Chem 19:301–303

    CAS  Google Scholar 

  91. Larson DL, Hua M, Takemori AK, Portoghese PS (1993) Possible contribution of a glutathione conjugate to the long-duration action of β-funaltrexamine. J Med Chem 36:3669–3673

    CAS  Google Scholar 

  92. Spetea M, Friedmann T, Riba P, Schütz J, Wunder G, Langer T, Schmidhammer H, Fürst S (2004) In vitro opioid activity profiles of 6-amino acid substituted derivatives of 14-O-methyloxymorphone. Eur J Pharmacol 483:301–308

    CAS  Google Scholar 

  93. Al-Khrasani M, Spetea M, Friedmann T, Riba P, Kiraly K, Schmidhammer H, Fürst S (2007) DAMGO and 6β-glycine substituted 14-O-methyloxymorphone but not morphine show peripheral, preemptive antinociception after systemic administration in a mouse visceral pain model and high intrinsic efficacy in the isolated rat vas deferens. Brain Res Bull 74:369–375

    CAS  Google Scholar 

  94. Obara I, Makuch W, Spetea M, Schütz J, Schmidhammer H, Przewlocki R, Przewlocka B (2007) Local peripheral antinociceptive effects of 14-O-methyloxymorphone derivatives in inflammatory and neuropathic pain in the rat. Eur J Pharmacol 558:60–67

    CAS  Google Scholar 

  95. Spetea M, Erlandsson Harris H, Berzetei-Gurske IP, Klareskog L, Schmidhammer H (2001) Binding, pharmacological and immunological profiles of the δ-selective opioid receptor antagonist HS 378. Life Sci 69:1775–1782

    CAS  Google Scholar 

  96. D'Ambrosio A, Noviello L, Negri L, Schmidhammer H, Quintieri F (2004) Effect of novel non-peptidic δ opioid receptor antagonists on human T and B cell activation. Life Sci 75:63–75

    Google Scholar 

  97. Tryoen-Toth P, Decaillot FM, Filliol D, Befort K, Lazarus LH, Schiller PW, Schmidhammer H, Kieffer BL (2005) Inverse agonism and neutral antagonism at wild type and constitutively active mutant δ opioid receptors. J Pharmacol Exp Ther 313:410–421

    CAS  Google Scholar 

  98. Jenny M, Winkler C, Spetea M, Schennach H, Schmidhammer H, Fuchs D (2008) Non-peptidic δ-opioid receptor antagonists suppress mitogen-induced tryptophan degradation in peripheral blood mononuclear cells in vitro. Immunol Lett 118:82–87

    CAS  Google Scholar 

  99. Cao CQ, Hong YG, Dray A, Perkins MN (2001) Selective depression of nociceptive responses of dorsal horn neurones by SNC80 in a perfused hindquarter preparation of adult mouse. Neuroscience 107:329–338

    CAS  Google Scholar 

  100. Cao CQ, Hong YG, Dray A, Perkins MN (2001) Spinal δ opioid receptors mediate suppression of systemic SNC80 on excitability of the flexor reflex in normal and inflamed rat. Eur J Pharmacol 418:79–87

    CAS  Google Scholar 

  101. Shahbazian A, Heinemann A, Schmidhammer H, Beubler E, Holzer-Petsche U, Holzer P (2002) Involvement of µ- and κ-, but not δ-opioid receptors in the peristaltic motor depression caused by endogenous and exogenous opioids in the guinea-pig intestine. Br J Pharmacol 135:741–750

    CAS  Google Scholar 

  102. Arakawa K, Akami T, Okamoto M, Nakajima H, Mitsuo M, Nakai I, Oka T, Nagase H, Matsumoto S (1992) Immunosuppressive effects of δ-opioid receptor antagonist on xenogeneic mixed lymphocyte response. Transplant Proc 24:696–697

    CAS  Google Scholar 

  103. Arakawa K, Akami T, Okamoto M, Akioka K, Akai I, Oka T, Nagase H (1993) Immunosuppression by δ opioid receptor antagonist. Transplant Proc 25:738–740

    CAS  Google Scholar 

  104. Linner KM, Stickney BJ, Quist HE, Sharp BM, Portoghese PS (1998) The δ1 opioid receptor antagonist, 7-benzylspiroindanylnaltrexone, prolongs renal allograft survival in a rat model. Eur J Pharmacol 354:R3–R5

    CAS  Google Scholar 

  105. Gavériaux-Ruff C, Filliol D, Simonin F, Matthes HWD, Kieffer BL (2001) Immunosuppression by δ-opioid antagonist naltrindole: δ- and triple µ/δ/κ-opioid receptor knockout mice reveal a nonopioid activity. J Pharmacol Exp Ther 298:1193–1198

    Google Scholar 

  106. Winkler C, Neurauter G, Schroecksnadel K, Wirleitner B, Fuchs D (2006) Immunomodulatory effects of plant extracts. In: Govil JN, Singh VK, Arunachalam C (eds) Recent progress in medicinal plants, vol 11. Studium, Houston, pp 139–158

    Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Austrian Science Fund (P11382, P12668, P15481, and P21350), European community (EPILA, QLK6-1999-02334), National Institute on Drug Abuse (N01DA-1-8816), and Drug Evaluation Committee of the College on Problems of Drug Dependence of the USA (N01DA-1-7725).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Helmut Schmidhammer .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Schmidhammer, H., Spetea, M. (2010). Synthesis of 14-Alkoxymorphinan Derivatives and Their Pharmacological Actions. In: Nagase, H. (eds) Chemistry of Opioids. Topics in Current Chemistry, vol 299. Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2010_77

Download citation

Publish with us

Policies and ethics