Recent advances in the development of 14-Alkoxy substituted morphinans as potent and safer opioid analgesics

Current Medicinal Chemistry

Volumn 19, Issue 15, 2012, Pages 2442-2457

  Spetea, M ^a   Schmidhammer, H ^a  

^a UNIVERSITY OF INNSBRUCK   (Austria)

Author keywords

14 Alkoxymorphinans; Affinity; Agonist; Analgesia; Antinociceptive potency; Chemistry; Morphine; Opioid receptors; Pain; Selectivity; Structure activity relationship; opioid agonists

Indexed keywords

14 ALKOXYMORPHINAN; 14 ETHOXYMETOPON; 14 METHOXYMETOPON; 14 O METHYLOXYMORPHONE; 14 PHENYLPROPOXYMETOPON; AMINO ACID; ANTINOCICEPTIVE AGENT; BETA FUNALTREXAMINE; BUPRENORPHINE; BUTORPHANOL; CODEINE; CYPRODIME; HYDROMORPHONE; LEVORPHANOL; MORPHINAN DERIVATIVE; MORPHINE; MU OPIATE RECEPTOR; MU OPIATE RECEPTOR AGONIST; N,N DIMETHYLFORMAMIDE; NALOXONE; NALOXONE PLUS OXYCODONE; NALTREXONE; NARCOTIC ANALGESIC AGENT; OXYCODONE; OXYMORPHONE; SUFENTANIL; UNCLASSIFIED DRUG;

ALCOHOLISM; ALKYLATION; ARTICLE; BINDING AFFINITY; BINDING ASSAY; BRADYCARDIA; CHEMICAL MODIFICATION; DRUG SYNTHESIS; ENTEROPATHY; HUMAN; HYPOTENSION; IC 50; IN VITRO STUDY; IN VIVO STUDY; METHYLATION; NONHUMAN; OPIATE ADDICTION; PAIN; RECEPTOR AFFINITY; RESPIRATION DEPRESSION; STRUCTURE ACTIVITY RELATION;

EID: 84860669844     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986712800269308     Document Type: Article

References (89)

1. Breivik, H.; Collett B.; Ventafridda, V.; Cohen, R.; Gallacher, D. Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. Eur. J. Pain, 2006, 10(4), 287-333.
2. Marcus, D.A.; Cope, D.K.; Deodhar, A.; Payne, R. Chronic pain: An atlas of investigation and management; Clinical Publishing: Oxford, 2009.
3. Inturrisi, C.E. Clinical pharmacology of opioids for pain. Clin. J. Pain, 2002, 18(4 Suppl), S3-13. (Pubitemid 34815390)
4. Portenoy, R.K. Treatment of cancer pain. Lancet, 2011, 377(9784), 2236-2247.
5. Knapp, R.J.; Malatynska, E.; Collins, N.; Fang, L.; Wang, J.Y.; Hruby, V.J. Molecular biology and pharmacology of cloned opioid receptors. FASEB J., 1995, 5(9), 516-525.
6. Kieffer, B.L.; Evans, C.J. Opioid receptors: From binding sites to visible molecules in vivo. Neuropharmacol., 2009, 56(Suppl 1), 205-212.
7. Mansour, A.; Fox C.A.; Akil H.; Watson S.J. Opioid-receptor mRNA expression in the rat CNS: Anatomical and functional implications. Trends Neurosci., 1995, 18(2), 22-29.
8. McCarthy, L.; Wetzel, M.; Sliker, J.K.; Eisenstein, T.K; Rogers, T.J. Opioids, opioid receptors, and the immune response. Drug Alcohol Depend., 2001, 62(2), 111-123. (Pubitemid 32195501)
9. Stein, C. Opioid receptors on peripheral sensory neurons. Adv. Exp. Med. Bio., 2003, 521, 69-76. (Pubitemid 36535165)
10. Holzer, P. Opioid receptors in the gastrointestinal tract. Regul. Pept., 2009, 155(1-3), 11-17.
11. Mayyas, F.; Fayers, P.; Kaasa S.; Dale O.J. A systematic review of oxymorphone in the management of chronic pain. Pain Symptom Manage., 2010, 39(2), 296-308.
12. Benyamin, R.; Trescot, A.M.; Datta, S.; Buenaventura, R.; Adlaka, R.; Sehgal, N.; Glaser, S.E.; Vallejo, R. Opioid complications and side effects. Pain Physician, 2008, 11(2 Suppl), S105-120. (Pubitemid 351682081)
13. Noble M.; Tregear S.J.; Treadwell J.R.; Schoelles K.J. Long-term opioid therapy for chronic noncancer pain: A systematic review and meta-analysis of efficacy and safety. Pain Symptom Manage., 2008, 35(2), 214-228.
14. Nicholson, B. Benefits of extended-release opioid analgesic formulations in the treatment of chronic pain. Pain Pract., 2009, 9(1), 71-81.
15. Nelson, L.; Schwaner R. Transdermal fentanyl: Pharmacology and toxicology. J. Med. Toxicol., 2009, 5(4), 230-241.
16. Simpson, K.; Leyendecker, P.; Hopp, M.; Müller-Lissner, S.; Löwenstein, O.; De Andrés, J.; Troy Ferrarons, J.; Bosse, B.; Krain, B.; Nichols, T.; Kremers, W.; Reimer, K. Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain. Curr. Med. Res. Opin., 2008, 24(12), 3503-3512.
17. Vadivelu, N.; Timchenko, A.; Huang, Y.; Sinatra, R. Tapentadol extendedrelease for treatment of chronic pain: A review. J. Pain Res., 2011, 4, 211-218.
18. Razdan, R.K.; Ghosh, A.C. 17-Cyclobutylmethyl-4,5a-epoxy-3-hydroxy-14- methoxy-8a-methylmorphinan-6-one, and treating pain with it. U.S. Patent 4,232,028, 1980.
19. Kobylecki, R.J.; Carling, R.W.; Lord, J.A.H.; Smith, C.F.C.; Lane, A.C. Common anionic receptor site hypothesis: Its relevance to the antagonist action of naloxone. J. Med. Chem., 1982, 25(2), 116-120. (Pubitemid 12106628)
20. Seki, I. Studies on the morphine alkaloids. 8. The preparation of the (-)-3,4,14-trihydroxymorphinan derivatives. Yakugaku Zasshi, 1964, 84, 615-620.
21. Schmidhammer, H.; Aeppli, L.; Atwell, L.; Fritsch, F.; Jacobson, A.E.; Nebuchla, M.; Sperk, G. 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., 1984, 27(12), 1575-1579. (Pubitemid 15177896)
22. Schmidhammer, H.; Krassnig, R. Synthesis and biological evaluation of 14-alkoxymorphinans. 6. 14-O-Ethyloxymorphone (= (-)-4,5a-epoxy-14-ethoxy-3- hydroxy-N-methylmorphinan-6-one). Sci. Pharm., 1990, 58, 255-257. (Pubitemid 20358287)
23. Lattanzi, R.; Spetea, M.; Schüllner, F.; Rief, S.B.; Krassnig, R.; Negri, L.; Schmidhammer, H. 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., 2005, 48(9), 3372-3378. (Pubitemid 40637205)
24. Riba, P.; Friedmann, T.; Király K.P.; Al-Khrasani, M.; Sobor, M.; Asim, M.F.; Spetea, M.; Schmidhammer, H.; Fürst, S. Novel approach to demonstrate high efficacy of μ opioids in the rat vas deferens: A simple model of predictive value. Brain Res. Bull., 2010, 81(1), 178-184.
25. 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. 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., 2005, 312(2), 609-618. (Pubitemid 40189558)
26. Spetea, M.; Bohotin, C.R.; Asim, M.F.; Stübegger, K.; Schmidhammer, H. In vitro and in vivo pharmacological profile of the 5-benzyl analogue of 14-methoxymetopon, a novel μ opioid analgesic with reduced propensity to alter motor function. Eur. J. Pharm. Sci., 2010, 41(1),125-135.
27. Small, L.; Fitch, H.M.; Smith W.E. Addition of organomagnesium halides to pseudocodeine types. II. Preparation of nuclear alkylated morphine derivatives. J. Am. Chem. Soc., 1936, 58(9), 1457-1463.
28. Eddy, N.B. Metopon hydrochloride (Methyldihydromorphinone hydrochloride). Can. Med. Assoc. J., 1948, 58, 79-80.
29. Boden, R.M.; Gates, M.; Ho, S.P.; Sundararaman, P. Derivatives of the thebaine anion. 1. Structure of metopon. A direct demonstration. J. Org. Chem., 1982, 47(7), 1347-1349. (Pubitemid 12072993)
30. Schmidhammer, H.; Fritsch F.; Burkhard, W.P.; Eggstein-Aeppli, L.; Hefti, F.; Holck, M.I. (-)-N-[(Cyclopropyl)methyl]-3,4-dimethoxy-5-methylmorphinan-6- one, an opioid agonist with preference for kappa opioid receptors. Helv. Chim. Acta, 1988, 71(3), 642-647.
31. Schmidhammer, H.; Deeter J.B.; Jones, N.D.; Leander, J.D.; Schoepp, D.D.; Swartzendruber, J.K. Synthesis, structure elucidation, and pharmacological evaluation of 5-methyl-oxymorphone (= 4,5a-epoxy-3,14-dihydroxy-5,17- dimethylmorphinan-6-one). Helv. Chim. Acta, 1988, 71(7), 1801-1804.
32. Schmidhammer, H.; Schratz, A.; Mitterdorfer, J. Synthesis and biological evaluation of 14-alkoxymorphinans. 8. 14-Methoxymetopon, an extremely potent opioid agonist. Helv. Chim. Acta, 1990, 73(6), 1784-1787. (Pubitemid 20303224)
33. Schütz, J; Spetea, M.; Koch, M.; Aceto, M.D.; Harris, L.S.; Coop, A.; Schmidhammer, H. Synthesis and biological evaluation of 14-alkoxymorphinans. 20. 14-Phenylpropoxymetopon: An extremely powerful analgesic. J. Med. Chem., 2003, 46(19), 4182-4187. (Pubitemid 37122460)
34. Gates, M.; Boden, R.M.; Sundararaman, P. 1989. Derivatives of the thebaine anion. 2. 5-Methylmorphine, 5-methylcodeine, 5-methylheroin, and some related compounds. J. Org. Chem., 1989, 54(4), 972-974. (Pubitemid 19068888)
35. Fürst, S.; Búzás, B.; Friedmann, T.; Schmidhammer, H.; Borsodi, A. Highly potent novel opioid receptor agonist in the 14-alkoxymetopon series. Eur. J. Pharmacol., 1993, 236, 209-215. (Pubitemid 23158299)
36. Spetea, M.; Tóth, F.; Schütz, J.; Ötvös, F.; Tóth, G.; Benyhe, S.; Borsodi, A.; Schmidhammer, H. Binding characteristics of [3H]14-methoxymetopon, a high affinity μ-opioid receptor agonist. Eur. J. Neurosci., 2003, 18(2), 290-295.
37. Mahurter, L.; Garceau, C.; Marino, J.; Schmidhammer, H.; Toth, G.; Pasternak, G.W. Separation of binding affinity and intrinsic activity of the potent μ-opioid 14-methoxymetopon. J. Pharmacol. Exp. Ther., 2006, 319(1), 247-253. (Pubitemid 44455129)
38. Zernig, G.; Saria, A.; Krassnig, R.; Schmidhammer, H. Signal transduction efficacy of the highly potent μ-opioid agonist 14-methoxymetopon. Life Sci., 2000, 66(19), 1871-1877. (Pubitemid 30198592)
39. Greiner, E.; Spetea, M.; Krassnig, R.; Schüllner, F.; Aceto, M.; Harris, L.S.; Traynor, J.R.; Woods, J.H.; Coop, A.; Schmidhammer, H. 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., 2003, 46(9), 1758-1763. (Pubitemid 36444228)
40. King, M.A.; Su, W.; Nielan, C.; Chang, A.H.; Schütz, J.; Schmidhammer, H.; Pasternak, G.W. 14-Methoxymetopon, a very potent μ-opioid analgesic with an unusual pharmacological profile. Eur. J. Pharmacol., 2003, 459(2-3), 203-209. (Pubitemid 36078322)
41. Király, K.P.; Riba, P.; D'Addario, C.; Di Benedetto, M.; Landuzzi, D.; Candelotti, S.; Romualdi, P.; Fürst, S. 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., 2006, 70(3), 233-239. (Pubitemid 44067348)
42. Urigüen, L.; Fernandez, B.; Romero, E.M.; De Pedro, N.; Delgado, M.J.; Guaza, C.; Schmidhammer, H.; Viveros M.P. 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., 2002, 57(5), 661-666. (Pubitemid 34240412)
43. Freye, E.; Schmidhammer, H.; Latasch L. 14-Methoxymetopon, a potent opioid, induces no respiratory depression, less sedation, and less bradycardia than sufentanil in the dog. Anesth. Analg., 2000, 90(6), 1359-1364. (Pubitemid 30351337)
44. Bileviciute-Ljungar, I.; Spetea, M.; Guo, Y.; Schütz, J.; Windisch, P.; Schmidhammer, H. Peripherally mediated antinociception of the μ-opioid receptor agonist 2-[(4,5a-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., 2006, 317(1), 220-227.
45. Stegmann, G.F. Etorphine-halothane anaesthesia in two five-year-old African elephants (Loxodonta africana). J. S. Afr. Vet. Assoc., 1999, 70(4), 164-166. (Pubitemid 30161069)
46. Sterken, J.; Troubleyn, J.; Gasthuys, F.; Maes, V.; Diltoer, M.; Verborgh, C. Intentional overdose of large animal immobilon. Eur. J. Emerg. Med., 2004, 11(5), 298-301.
47. Avdeef, A.; Testa, B. Physicochemical profiling in drug research: A brief survey of the state-of-the-art of experimental techniques. Cell. Mol. Life Sci., 2002, 59(10), 1681-1689. (Pubitemid 35346972)
48. Casy, A.F.; Parfitt, R.T. Opioid analgesics: Chemistry and receptors; Plenum Press: New York, 1986.
49. Schmidhammer, H. Opioid receptor antagonists. In: Progress in Medicinal Chemistry; Ellis; G.P.; Luscombe, D.K.; Oxford, A.W. Eds.; Elsevier, New York, 1998; Vol. 35, pp. 83-132.
50. Dean, R.L.III; Bilsky, E.J.; Negus, S.S. Opioid receptors and antagonists: From bench to clinic; Humana Press: New York, 2009.
51. Schmidhammer, H.; Burkard, W.P.; Eggstein-Aeppli, L.; Smith, C.F.C. (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., 1989, 32(2), 418-421. (Pubitemid 19061887)
52. Ni, Q.; Xu, H.; Partilla, J. S.; Rice, K. C.; Matecka, D.; Calderon, S. N.; Porreca, F.; Lai, J.; Schmidhammer, H.; Krassnig, R.; Rothman, R.B. Opioid peptide receptor studies. 9. Identification of a novel non μ non like opioid peptide binding site in rat brain. Peptides, 1998, 19(6), 1079-1090. (Pubitemid 28383807)
53. Spetea, M.; Ötvös, F.; Tóth, G.; Nguyen, T. M.-D.; Schiller, P. W.; Vogel, Z.; Borsodi, A. Interaction of agonist peptide [3H]Tyr-D-Ala-Phe-Phe-NH2 with μ opioid receptor in rat Brain and CHO-μ/1 cell line. Peptides, 1998, 19(6), 1091-1098. (Pubitemid 28383808)
54. Hutcheson, D. M.; Sánchez-Blazquez, P.; Rodriguez-Diaz, M.; Garzon, J.; Schmidhammer, H.; Borsodi, A.; Roques, B. P.; Maldonado, R. Use of selective antagonists and antisense oligonucleotides to evaluate the mechanisms of BUBU antinociception. Eur. J. Pharmacol., 1999, 383(1), 29-37. (Pubitemid 29509819)
55. Márki, Á.; Monory, K.; Ötvös, F.; Tóth, G.; Krassnig, R.; Schmidhammer, H.; Traynor, J. R.; Roques, B. P.; Maldonado, R.; Borsodi, A. μ Opioid receptor specific antagonist cyprodime: Characterization by in vitro radioligand and [35S]GTP?S binding assays. Eur. J. Pharmacol., 1999, 383(2), 209-214.
56. Shahbazian, A.; Heinemann, A.; Schmidhammer, H.; Beubler, E.; Holzer-Petsche, U.; Holzer, P. Involvement of μ and k, but not 8 Opioid receptors in the peristaltic motor depression caused by endogenous and exogenous opioids in the guinea-pig intestine. Br. J. Pharmacol., 2002, 135(3), 741-750. (Pubitemid 34177652)
57. Starowicz, K.; Przewlocki, R.; Gispen, W. H.; Przewlocka, B. Modulation of melanocortin-induced changes in spinal nociception by μ opioid receptor agonist and antagonist in neuropathic rats. NeuroReport, 2002, 13(18), 2447-2452. (Pubitemid 36143542)
58. Freye, E.; Latasch L.; Schmidhammer, H. Pharmacodynamic effects of S-(+)-ketamine on EEG, evoked potentials and respiration. A study in the awake dog. Anaesthesist, 1992, 41(9), 527-533.
59. Henry, B., Fox, S.H., Crossman, A.R., Brotchie J.M. μ and d Opioid receptor antagonists reduce levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Exper. Neurol., 2001, 171(1), 139-146. (Pubitemid 32848452)
60. Schmidhammer, H.; Smith, C.F.C.; Erlach, D.; Koch, M.; Krassnig, R.; Schwetz, W.; Wechner, C. Synthesis and biological evaluation of 14-alkoxymorphinans. 3. Extensive Study on Cyprodime-Related Compounds. J. Med. Chem., 1990, 33(4), 1200-1206. (Pubitemid 20115424)
61. Spetea, M.; Schüllner, F.; Moisa, R.C.; Berzetei-Gurske, I.P.; Schraml, B.; Dörfler, C.; Aceto, M.D.; Harris, L.S.; Coop, A.; Schmidhammer, H. 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., 2004, 47(12), 3242-3247. (Pubitemid 38702716)
62. Pasternak, G.W.; Hahn, E.F. Long-acting opiate agonists and antagonists: 14-hydroxydihydromorphinone hydrazones. J. Med. Chem. 1980, 23(6), 674-676. (Pubitemid 11237827)
63. Varga, E.; Toth, G.; Benyhe, S.; Hosztafi, S.; Borsodi A. Synthesis and binding of 3H-oxymorphazone to rat brain membranes. Life Sci., 1987, 40(16), 1579-1588. (Pubitemid 17046054)
64. Krizsan, D.; Varga, E.; Hosztafi, S.; Benyhe, S.; Szucs, M.; Borsodi A. Irreversible blockade of the high and low affinity (3H)naloxone binding sites by C-6 derivatives of morphinan-6-ones. Life Sci., 1991, 48(5), 439-451.
65. Fürst, Z.; Borsodi, A.; Friedmann, T.; Hosztafi, S. 6-Substituted oxycodone derivatives have strong antinociceptive effects and block irreversibly the low affinity [3H]-naloxone binding sites in rat brain. Pharm. Res., 1992, 25(1), 31-32.
66. Fürst, S.; Hosztafi, S.; Friedmann, T. Structure-activity relationships of synthetic and semisynthetic opioid agonists and antagonists. Curr. Med. Chem., 1995, 1, 423-440.
67. Oldenziel, O.H.; van Leusen, D.; van Leusen, A.M. 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., 1977, 42(19), 3114-3118.
68. Greiner, E.; Schottenberger, H.; Wurst, K.; Schmidhammer, H. Novel class of morphinans with acrylonitrile incorporated substructures as key intermediates for non-oxygen-bridged opioid ligands. J. Am. Chem. Soc., 2001, 123(16), 3840-3841. (Pubitemid 32879554)
69. Spetea, M.; Greiner, E.; Aceto. M.D.; Harris, L.S.; Coop, A.; Schmidhammer, H. Effect of a 6-cyano substituent in 14-oxygenated Nmethylmorphinans on opioid receptor binding and antinociceptive potency. J. Med. Chem., 2005, 48(15), 5052-5055. (Pubitemid 41033146)
70. Schütz, J.; Windisch, P.; Kristeva, E.; Wurst, K.; Ongania, K-H.; Horvath, U.I.E.; Schottenberger, H.; Laus, G.; Schmidhammer, H. Mechanistic diversity of the van Leusen reaction applied to 6-ketomorphinans and synthetic potential of the resulting acrylonitrile substructures. J. Org. Chem., 2005, 70(13), 5323-5326. (Pubitemid 40863942)
71. Stein, C.; Schäfer, M.; Machelska, H. Attacking pain at its source: New perspectives on opioids. Nature Med., 2003, 9(8), 1003-1008. (Pubitemid 37021779)
72. Kapitzke, D.; Vetter, I.; Cabot, P.J. Endogenous opioid analgesia in peripheral tissues and the clinical implications for pain control. Ther. Clin. Risk Manag., 2005, 1(4), 279-297.
73. Stein, C.; Clark, J.D.; Oh, U.; Vasko, M.R.; Wilcox, G.L.; Overland, A.C.; Vanderah, T.W.; Spencer, R.H. Peripheral mechanisms of pain and analgesia. Brain. Res. Rev., 2009, 60(1), 90-113.
74. Hua, S.; Cabot, P.J. Mechanisms of peripheral immune-cell-mediated analgesia in inflammation: Clinical and therapeutic implications. Trends Pharmacol. Sci., 2010, 31(9), 427-433.
75. Sehgal, N.; Smith, H.S.; Manchikanti, L. Peripherally acting opioids and clinical implications for pain control. Pain Physician, 2011, 14(3), 249-258.
76. Stein, C.; Machelska, H. Modulation of peripheral sensory neurons by the immune system: Implications for pain therapy. Pharmacol Rev., 2011, 63(4), 860-881.
77. DeHaven-Hudkins, D.L.; Dolle, R.E. Peripherally restricted agonists as novel analgesic agents. Curr. Pharm. Design, 2004, 10(7), 743-757. (Pubitemid 38292402)
78. Vadivelu, N.; Mitra, S.; Hines, R.L. Peripheral opioid receptor agonists for analgesia: A comprehensive review. J. Opioid Manag., 2011, 7(1), 55-68.
79. Iorio, M.A.; Frigini V. Narcotic agonist/antagonist properties of quaternary diastereoisomers derived from oxymorphone and naloxone. Eur. J. Med. Chem., 1984, 19(4), 301-303. (Pubitemid 14007999)
80. Brown, D.R.; Goldberg, L.I. The use of quaternary narcotic antagonists in opiate research. Neuropharmacol., 1985, 24(3), 181-191. (Pubitemid 15051584)
81. Botros, S.; Lipkowski, A.W.; Larson, D.L.; Stark, A.P.; Takemori, A.E.; Portoghese, P.S. Opioid agonist and antagonist activities of peripherally selective derivatives of naltrexamine and oxymorphamine. J. Med. Chem., 1989, 32(9), 2068-2071. (Pubitemid 19224167)
82. Larson, D.L.; Hua, M.; Takemori, A.K.; Portoghese, P.S. Possible contribution of a glutathione conjugate to the long-duration action of β-funaltrexamine. J. Med. Chem., 1993, 36(23), 3669-3673. (Pubitemid 24004365)
83. Portoghese, P.S.; Farouz-Grant, F.; Sultana, M.; Takemori, A.E. (1995) 7'-Substituted amino acid conjugates of naltrindole. Hydrophilic groups as determinants of selective antagonism of d1 opioid receptor-mediated antinociception in mice. J. Med. Chem., 1995, 38(3), 402-407.
84. Schütz, J.; Brandt, W.; Spetea, M.; Wurst, K.; Wunder, G.; Schmidhammer, H. Synthesis of 6-amino acid substituted derivatives of the highly potent analgesic 14-O-methyloxymorphone. Helv. Chim. Acta, 2003, 86(6), 2142-2148. (Pubitemid 36899523)
85. Spetea, M.; Friedmann, T.; Riba, P.; Schütz, J.; Wunder, G.; Langer, T.; Schmidhammer H.; Fürst S. In vitro opioid activity profiles of 6-amino acid substituted derivatives of 14-O-methyloxymorphone. Eur. J. Pharmacol., 2004, 483(2-3), 301-308. (Pubitemid 38068414)
86. 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. 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., 2005, 312(2), 609-618. (Pubitemid 40189558)
87. Spetea, M.; Windisch, P.; Guo, Y.; Bileviciute-Ljungar, I.; Schütz, J.; Asim, M.F.; Berzetei-Gurske, I.P.; Riba, P.; Kiraly, K.; Fürst, S.; Al-Khrasani, M.; Schmidhammer, H. Synthesis and pharmacological activities of 6-glycine substituted 14-phenylpropoxymorphinans, a novel class of opioids with high opioid receptor affinities and antinociceptive potencies. J. Med. Chem., 2011, 54(4), 980-988.
88. Al-Khrasani, M.; Spetea, M.; Friedmann, T.; Riba, P.; Kiraly, K.; Schmidhammer, H.; Fürst, S. DAMGO and 6β-glycine substituted 14-Omethyloxymorphone 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., 2007, 74(5), 369-375. (Pubitemid 47368888)
89. Obara, I.; Makuch, W.; Spetea, M.; Schütz, J.; Schmidhammer, H.; Przewlocki, R.; Przewlocka, B. Local peripheral antinociceptive effects of 14-O-methyloxymorphone derivatives in inflammatory and neuropathic pain in the rat. Eur. J. Pharmacol., 2007, 558(1-3), 60-67. (Pubitemid 46328870)