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Chemistry and synthesis of major opium alkaloids: a comprehensive review

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Abstract

Among analgesic drugs, the opioid class of compounds still remains one of the most important medicines for severe and chronic pain treatment. Hence, developing novel and effective synthetic method of morphine and its related compounds is still an important task in modern synthetic organic chemistry. Achieving this goal demands a comprehensive knowledge of these valuable alkaloids. The present review study aims to summarize the history of five major opioid alkaloids and their pharmacologic effects, as well as various synthetic and biosynthetic methods.

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References

  1. P.R. Blakemore, J.D. White, Morphine, the Proteus of organic molecules. Chem. Commun. 11, 1159–1168 (2002)

    Article  CAS  Google Scholar 

  2. G.D. Busse, D.J. Triggle, Morphine, Drugs: The Straight Facts, (Chelsea House Publishing, 2006), pp. 8–18

  3. G.M. Heyman, “Opiate Use and Abuse, History of”, International Encyclopedia of the Social & Behavioral Sciences, 2nd edn. (Elsevier, Oxford, 2015), pp. 236–242

    Book  Google Scholar 

  4. P.L. Schiff Jr., Opium and its alkaloids. Am. J. Pharm. Educ. 66, 186–193 (2002)

    Google Scholar 

  5. D. Mani, S.S. Dhawan, Scientific basis of therapeutic uses of opium poppy (PapaverSomniferum) in a Ayurveda. Acta Hort. 1036, 175–180 (2014)

    Article  Google Scholar 

  6. J.P. Hoffmann, The historical shift in the perception of opiates: from medicine to social menace. J. Psychoact. Drugs 22, 53–62 (1990)

    Article  CAS  Google Scholar 

  7. J.M. Brownstein, A brief history of opiates, opioid peptides, and opioid receptors. Proc. Natl. Acad. Sci. USA 90, 5391–5393 (1993)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. L.W. Fleming, A medical bouquet poppies, cinchona and willow. Scot. Med. J. 44, 176–179 (1999)

    Article  CAS  PubMed  Google Scholar 

  9. M. Obladen, Lethal lullabies: a history of opium usein infants. J. Hum. Lact. 32, 75–85 (2015)

    Article  PubMed  Google Scholar 

  10. A. Moosavyzadeh, F. Ghaffari, S.H. Mosavat, A. Zargaran, A. Mokri, S. Faghihzadeh, M. Naseri, The medieval Persian manuscript of Afyunieh: the first individual treatise on the opium and addiction in history. J. Integr. Med. 16, 77–83 (2018)

    Article  PubMed  Google Scholar 

  11. J.C. Kramer, Opium rampant: medical use, misuse and abuse in britain and the west in the 17th and 18th centuries. Addiction 74, 377–389 (1979)

    Article  CAS  Google Scholar 

  12. G.B. Stefano, N. Pilonis, R. Ptacek, R.M. Kream, Reciprocal evolution of opiate science from medical and cultural perspectives. Med. Sci. Monit. 23, 2890–2896 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  13. D. Macht, The history of opium and some of its preparations and alkaloids. JAMA 64, 477–481 (1915)

    Article  CAS  Google Scholar 

  14. G.W. Pasternak, Y.X. Pan, Mu opioids and their receptors: evolution of a concept. Pharmacol. Rev. 65, 1257–1317 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. K. Brook, J. Bennett, S.P. Desai, The structure of morphine: an 8000-year journey, from resin to de-novo synthesis. J. Anesth. Hist. 3(2), 50–55 (2017)

    Article  PubMed  Google Scholar 

  16. M. Heydari, H.M. Hashempur, A. Zargaran, Medicinal aspects of opium as described in Avicenna’s Canon of Medicine. Acta Med. Hist. Adriat. 11(1), 101–112 (2013)

    PubMed  Google Scholar 

  17. F. Ghaffari, M. Naseri, M. Movahhed, A. Zargaran, Spinal traumas and their treatments according to Avicenna’s Canon of Medicine. World Neurosurg. 84(1), 173–177 (2015)

    Article  PubMed  Google Scholar 

  18. S. Hamarneh, Pharmacy in medieval Islam and the history of drug addiction. Med Hist. 16(3), 226–237 (1972)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. H. Khademi, F. Kamangar, P. Brennan, R. Malekzadeh, Opioid therapy and its side effects: a review. Arch. Iran Med. 19, 870–876 (2016)

    PubMed  Google Scholar 

  20. A. Rosenblum, L.A. Marsch, H. Joseph, R.K. Portenoy, Opioids and the treatment of chronic pain: controversies, current status, and future directions. Exp. Clin. Psychopharmacol. 16, 405 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  21. J.J. Hobbs, Troubling fields: the opium poppy in Egypt. Geogr. Rev. 88(1), 64–85 (2010)

    Article  Google Scholar 

  22. P.G. Kritikos, S.P. Papadaki, The history of the poppy and of opium and their expansion in antiquity in the eastern Mediterranean area. Bull. Narc. 19(3), 17–38 (1967)

    Google Scholar 

  23. S. Neal, Opium and migration: jardine matheson’s imperial connections and the recruitment of Chinese labour for Assam, 1834–39. Mod. Asian Stud. 51, 1626–1655 (2017)

    Article  Google Scholar 

  24. K. Reist, Opium wars (1839–1842, 1856–1860), in The encyclopedia of war, 1st edn. (Blackwell Publishing Ltd, Hoboken, 2011)

    Google Scholar 

  25. M. Bagheria, M.R. Taheria, M. Farhadpoura, H. Rezadoosta, A. Ghassempoura, H.Y. Aboul-Eneinb, Evaluation of hydrophilic interaction liquid chromatographystationary phases for analysis of opium alkaloids. J. Chromatogr. A 1511, 77–84 (2017)

    Article  CAS  Google Scholar 

  26. E. Dehghan, B. Hosseini, H. Naghdi Badi, F. Shahriari Ahmadi, Application of conventional and new biotechnological approaches for improving of morphinane alkaloids production. J. Med. Plant. 9, 34–50 (2010)

    Google Scholar 

  27. A.L. Devereaux, S.L. Mercer, C.W. Cunningham, DARK classics in chemical neuroscience: morphine. ACS Chem. Neurosci. 9, 2395–2407 (2018)

    Article  CAS  PubMed  Google Scholar 

  28. E. Martinez-Fernandez, F. Aragon-Poce, C. Marquez-Espinos, A. Perez-Perez, The history of opiates. Int. Congr. Ser. 1242, 75–77 (2002)

    Article  Google Scholar 

  29. T.A. Alston, Morphine zwitterion. J. Anesth. Hist. 3, 69–70 (2017)

    Article  PubMed  Google Scholar 

  30. M. Freemantle, Morphine. Chem. Eng. News. 83, 90 (2005)

    Article  Google Scholar 

  31. T. Anderson, On the chemistry of opium. J. Chem. Soc. 15, 446–455 (1862)

    Article  Google Scholar 

  32. Oripavine, 34th ECDD, 6/3 (2006)

  33. P. Madadi, G. Koren, Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use. Pharmacogenomics 9(9), 1267–1284 (2008)

    Article  PubMed  Google Scholar 

  34. T.I. Kakhia, Alkaloids & Alkaloids Plants, (Industry Joint Research Center-Adana University-Turkey, 2012), pp. 295–338

  35. J.M.P.J. Garrido, C. Delerue-Matos, F. Borges, T.R.A. Macedo, A.M. Oliveira-Brett, Voltammetric oxidation of drugs of abuse, (II) codeine and metabolites. Electroanalysis 16(17), 1427–1433 (2004)

    Article  CAS  Google Scholar 

  36. N. MacDonald, S.M. MacLeod, Has the time come to phase out codeine? CMAJ 182(17), 1825–1825 (2010)

    Article  PubMed  PubMed Central  Google Scholar 

  37. C. Straube, S. Derry, K.C. Jackson, P.J. Wiffen, R.F. Bell, S. Strassels, S. Straube, Codeine, alone and with paracetamol (acetaminophen), for cancer pain (review). Cochrane Database Sys. Rev. 9, CD006601 (2014)

    Google Scholar 

  38. M.L. Fleming, M.A. Wanat, To prescribe codeine or not to prescribe codeine? J. Pain Palliat. Care Pharmacother. 28(3), 251–254 (2014)

    Article  PubMed  Google Scholar 

  39. S.C. Armstrong, K.L. Cozza, Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part II. Psychosomatics 44(6), 515–520 (2003)

    Article  CAS  PubMed  Google Scholar 

  40. Q.Y. Yue, J.O. Svensson, C. Alm, F. Sjöqvist, J. Säwe, Interindividual and interethnic differences in the demethylation and glucuronidation of codeine. Br. J. Clin. Pharm. 28, 629–637 (1989)

    Article  CAS  Google Scholar 

  41. R.B. Barber, H. Rapoport, Synthesis of thebaine and oripavine from codeine and morphine. J. Med. Chem. 18, 1074–1077 (1975)

    Article  CAS  PubMed  Google Scholar 

  42. R.E. Lister, Structure-activity requirements in some novel Thebaine-derived analgesics. J. Pharm. Pharmacol. 16(5), 364–366 (1964)

    Article  CAS  PubMed  Google Scholar 

  43. A. Lipp, D. Ferenc, C. Gütz, M. Geffe, N. Vierengel, D. Schollmeyer, H.J. Schäfer, S.R. Waldvogel, T. Opatz, A regio- and diastereoselective anodic Aryl-Aryl coupling in the biomimetic total synthesis of (−)-thebaine. Angew. Chem. 57(34), 11055–11059 (2018)

    Article  CAS  Google Scholar 

  44. S.C. Pinzaru, N. Leopold, I. Pavel, W. Kiefer, Raman, SERS and theoretical studies of papaverine hydrochloride and its neutral species. Spectrochim. Acta A 60, 2021–2028 (2004)

    Article  CAS  Google Scholar 

  45. J.C. Abber, T.F. Lue, B.R. Orvis, R.D. McClure, R.D. Williams, Diagnostic tests for impotence: a comparison of papaverine injection with the penile-brachial index and nocturnal penile tumescence monitoring. J. Urol. 135, 923–925 (1986)

    Article  CAS  PubMed  Google Scholar 

  46. X. Han, M. Lamshöft, N. Grobe, X. Ren, A.J. Fist, T.M. Kutchan, M. Spiteller, M.H. Zenk, The biosynthesis of papaverine proceeds via (S)-reticuline. Phytochemistry 71, 1305–1312 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. D.A. Guthrie, Studies on the synthesis of papaverine. Ph.D. Dissertation, McGill University, (1952)

  48. M.R. Gilliss, Papaverine-safety in use. J. Am. Geriatr. Soc. 21, 200–201 (1973)

    Article  CAS  PubMed  Google Scholar 

  49. M.S. Pathy, A.J. Reynolds, Papaverine and hepatotoxicity. Postgrad. Med. J. 56, 488–490 (1980)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. J. Yan, J.Q. Mi, J.T. He, Z.Q. Guo, M.P. Zhao, W.B. Chang, Development of an indirect competitive ELISA for the determination of papaverine. Talanta 66, 1005–1011 (2005)

    Article  CAS  PubMed  Google Scholar 

  51. C. Liu, Synthesis of clean cabbage like (111) faceted silver crystals for efficient surface-enhanced raman scattering sensing of papaverine. Anal. Chem. 90(16), 9805–9812 (2018)

    Article  CAS  PubMed  Google Scholar 

  52. P.C.G. Rida, D. LiVecche, A. Ogden, J. Zhou, R. Aneja, The noscapine chronicle: a pharmaco-historic biography of the opiate alkaloid family and its clinical applications. Med. Res. Rev. 35(5), 1072–1096 (2005)

    Article  CAS  Google Scholar 

  53. K.P. Nayak, E. Brochmann-Hanssen, E.L. Way, Biological disposition of noscapine I. J. Pharm. Sci. 54, 191–194 (1963)

    Article  Google Scholar 

  54. X. Chen, T.-T.T. Dang, P.J. Facchini, Noscapine comes of age. Phytochemistry 111, 7–13 (2015)

    Article  CAS  PubMed  Google Scholar 

  55. M. Mahmoudian, P. Rahimi-Moghaddam, The anti-cancer activity of noscapine: a review. Recent Pat. Anticancer Drug Discov. 4(1), 92–97 (2009)

    Article  CAS  PubMed  Google Scholar 

  56. Z.R. Yang, M. Liu, X.L. Peng, X.F. Lei, J.X. Zhang, W.G. Dong, Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro. Biochem. Biophys. Res. Commun. 421, 627–633 (2012)

    Article  CAS  PubMed  Google Scholar 

  57. A. Niazi, Adsorptive stripping differential pulse voltammetry for determination of trace amounts of noscapine in human plasma. J. Chin. Chem. Soc. 54, 1195–1200 (2007)

    Article  CAS  Google Scholar 

  58. H. Schmidhammer, E. Scherb-Bukowiecki, T.A. Mayer, Synthesis of benzazepine analogues of noscapine. Helv. Chim. Acta 77, 1590–1594 (1994)

    Article  CAS  Google Scholar 

  59. A.K. Manchukonda, P.K. Naik, B. Sridhar, S. Kantevari, Synthesis and biological evaluation of novel biaryl type a-noscapine congeners. Bioorg. Med. Chem. Lett. 24, 5752–5757 (2014)

    Article  CAS  PubMed  Google Scholar 

  60. Z.Z. Fang, K.W. Krausz, F. Li, J. Cheng, N. Tanaka, F.J. Gonzalez, Metabolic map and bioactivation of the anti-tumour drug noscapine. Br. J. Pharmacol. 167, 1271–1286 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. S. Klemenc, Noscapine as an adulterant in illicit heroin samples. Forensic Sci. Int. 108, 45–49 (2000)

    Article  CAS  PubMed  Google Scholar 

  62. S. Hosztafi, The history of heroin. Acta Pharm. Hung. 71(2), 233–242 (2001)

    CAS  PubMed  Google Scholar 

  63. J. Merry, A social history of heroin addiction. Br. J. Addict. 70, 307–310 (1975)

    Article  CAS  Google Scholar 

  64. J. Strang, T. Groshkova, N. Metrebian, New heroin-assisted treatment - recent evidence and current practices of supervised injectable heroin treatment in Europe and beyond, vol. 11 (European Monitoring Centre for Drugs and Drug Addiction, 2012)

  65. M.G. Miller, N. McCarthy, C.A. O’Boyle, M. Kearney, Continuous subcutaneous infusion of morphine vs. hydromorphone: a controlled trial. J. Pain Symptom Manag. 18, 9–16 (1999)

    Article  CAS  Google Scholar 

  66. M.G. Kumar, S. Lin, Hydromorphone: analytical methodologies for its determination. Curr. Anal. Chem. 4, 111–126 (2008)

    Article  CAS  Google Scholar 

  67. Y.J. Bao, W. Hou, X.Y. Kong, L. Yang, J. Xia, B.J. Hua, R. Knaggs, Hydromorphone for cancer pain. Cochrane Database Syst. Rev. 10(10), CD011108 (2016)

    PubMed  Google Scholar 

  68. S.V. Weinstein, A new extended release formulation (OROS®) of hydromorphone in the management of pain. Ther Clin Risk Manag. 5, 75–80 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  69. E. Prommer, Oxymorphone: a review. Support Care Cancer 14, 109–115 (2006)

    Article  PubMed  Google Scholar 

  70. F. Mayyas, P. Fayers, S. Kaasa, O. Dale, A systematic review of oxymorphone in the management of chronic pain. J. Pain Symptom Manag. 39, 296–308 (2010)

    Article  CAS  Google Scholar 

  71. R.S. Sinatra, D.M. Harrison, A comparison of oxycodone and fentanyl as narcotic supplements in general anesthesia. J. Clin. Anesth. 1, 253–258 (1989)

    Article  CAS  PubMed  Google Scholar 

  72. K.W. Chamberlin, R. Neville, J. Tan, Oral oxymorphone for pain management. Ann. Pharmacother. 41, 1144–1152 (2007)

    Article  CAS  PubMed  Google Scholar 

  73. N. Vadivelu, D. Chang, E.M. Helander, G.J. Bordelon, A. Kai, A.D. Kaye, D. Hsu, D. Bang, I. Julka, Ketorolac, oxymorphone, tapentadol, and tramadol. Anesthesiol. Clin. 35(2), e1–e20 (2017)

    Article  PubMed  Google Scholar 

  74. X. Ruan, K.F. Mancuso, A.D. Kaye, Revisiting oxycodone analgesia. Anesthesiol. Clin. 35(2), e163–e174 (2017)

    Article  PubMed  Google Scholar 

  75. K.L. Boyle, C.D. Rosenbaum, Oxycodone overdose in the pediatric population: case files of the university of massachusetts medical toxicology fellowship. J. Med. Toxicol. 10(3), 280–285 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  76. J.W. Mandema, R.F. Kaiko, B. Oshlack, R.F. Reder, D.R. Stanski, Characterization and validation of a pharmacokinetic model for controlled-release oxycodone. Br. J. Clin. Pharmacol. 42, 747–756 (1996)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. H. Kokki, M. Kokki, Central nervous system penetration of the opioid oxycodone, in Neuropathology of Drug Addictions and Substance Misuse. (Elsevier, Amsterdam, 2016), pp. 457–466

    Chapter  Google Scholar 

  78. E. Kalso, Oxycodone. J. Pain Symptom Manag. 29(5), 47–56 (2005)

    Article  CAS  Google Scholar 

  79. R. Huddart, M. Clarke, R.B. Altman, T.E. Klein, Oxycodone pathway, pharmacokinetics. PharmGKB Summary 28(10), 230–237 (2010)

    Google Scholar 

  80. C. Mannich, H. Löwenheim, Ueber zwei neue Reduktionsprodukte des Kodeins. Arch. Pharm. 258, 295–316 (1920)

    Article  CAS  Google Scholar 

  81. D. Krashin, N. Murinova, A. Trescot, Extended-release hydrocodone – gift or curse? J. Pain Res. 6, 53–57 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  82. S.L. Walsh, P.A. Nuzzo, M.R. Lofwall, J.R. Holtman, The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription opioid abusers. Drug Alcohol Depend. 98, 191–202 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. A. Saitman, R.L. Fitzgerald, L.M. McIntyre, Evaluation and comparison of postmortem hydrocodone concentrations in peripheral blood, central blood and liver specimens: a minimal potential for redistribution. Forensic Sci. Int. 247, 36–40 (2015)

    Article  CAS  PubMed  Google Scholar 

  84. F.S. Alshehri, A.Y. Hakami, Y.S. Althobaiti, Y. Sari, Effects of ceftriaxone on hydrocodone seeking behavior and glial glutamate transporters in rats. Behav. Brain Res. 347, 368–376 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. L. Day, K. Kleinschmidt, M.B. Forrester, S.Y. Feng, Comparison of unintentional exposures to codeine and hydrocodone reported to texas poison centers. J. Emerg. Med. 50, 744–752 (2016)

    Article  PubMed  Google Scholar 

  86. R.J. Defalque, A.J. Wright, The early history of methadone, myths and facts. Bull. Anesth. Hist. 25(3), 13–16 (2007)

    Article  PubMed  Google Scholar 

  87. F. Leri, A. Tremblay, R.E. Sorge, J. Stewart, Methadone maintenance reduces heroin- and cocaine-induced relapse without affecting stress-induced relapse in a rodent model of poly-drug use. Neuropsychopharmacology 29, 1312–1320 (2004)

    Article  CAS  PubMed  Google Scholar 

  88. “Methadone: what's the story?” Dublin, UISCE, 32, 1–34 (2003)

  89. A.B.M. Paul, L. Simms, A.M. Mahesan, The toxicology of methadone-related death in infants under 1 year: three case series and review of the literature. J. Forensic Sci. 62, 1414–1417 (2017)

    Article  CAS  PubMed  Google Scholar 

  90. J.M. Corkery, F. Schifano, A.H. Ghodse, A. Oyefeso, The effects of methadone and its role in fatalities. Hum. Psychopharmacol. Clin. Exp. 19(8), 565–576 (2004)

    Article  CAS  Google Scholar 

  91. R. Ojha, S.C. Bhatia, Tramadol dependence in a patient with no previous substance history. Prim. Care Companion J. Clin. Psychiatry (2010). https://doi.org/10.4088/PCC.09l00779ecr

    Article  PubMed  PubMed Central  Google Scholar 

  92. Tramadol, Expert Committee on Drug Dependence, Thirty-sixth Meeting. Geneva, WHO Technical Report Series 991 (2014)

  93. V. Varghese, T. Hudicky, A short history of the discovery and development of naltrexone and other morphine derivatives, in Natural Products in Medicinal Chemistry. (Wiley-VCH Verleg GmbH & Co. KGaA, New Jersey, 2014), pp. 225–250

    Chapter  Google Scholar 

  94. V. Beltran-Campos, M. Silva-Vera, M.L. Garcia-Campos, S. Diaz-Cintra, Effects of morphine on brain plasticity. Neurologia (English Edition) 30(3), 176–180 (2015)

    Article  CAS  Google Scholar 

  95. S. Benyhe, F. Zador, F. Otvos, Biochemistry of opioid (morphine) receptors: binding, structure and molecular modeling. Acta Biol Szeged. 59, 17–37 (2015)

    Google Scholar 

  96. P.A.J. Janssen, A review of the chemical features associated with strong morphine-like activity. Br. J. Anaesth. 34, 260–268 (1962)

    Article  CAS  PubMed  Google Scholar 

  97. A.M. Trescot, S. Datta, M. Lee, H. Hansen, Opioid pharmacology. Pain Physician 11, 133–153 (2008)

    Article  Google Scholar 

  98. B.L. Kieffer, C.J. Evans, Opioid receptors: from binding sites to visible molecules in vivo. Neuropharmacology 56, 205–212 (2009)

    Article  CAS  PubMed  Google Scholar 

  99. P.K. Janicki, Pharmacology of Morphine Metabolites. Curr. Pain Headache Rep. 1(264–270), 238 (1997)

    Google Scholar 

  100. A. Laux-Biehlmann, J. Mouheiche, J. Veriepe, Y. Goumon, Endogenous morphine and its metabolites in mammals: history, synthesis, localization and perspectives. Neuroscience 233, 95–117 (2013)

    Article  CAS  PubMed  Google Scholar 

  101. Y. Goumon, A. Laux-Biehlmann, A. Muller, D. Aunis, Central and peripheral endogenous morphine. An R Acad. Nac Farm. 75, 389–418 (2009)

    CAS  Google Scholar 

  102. A. Koneru, S. Satyanarayana, S. Rizwan, Current knowledge and future trends of endogenous opioids: three physiological role and receptors. Pharmacologyonline 1, 780–788 (2010)

    Google Scholar 

  103. I. Sora, G. Elmer, M. Funada, J. Pieper, X.F. Li, F.S. Hall, G.R. Uhl, μ opiate receptor gene dose effects on different morphine actions evidence for differential in vivo μ receptor reserve. Neuropsychopharmacology 25(1), 41–54 (2011)

    Article  Google Scholar 

  104. T.P. Su, T.C. Su, Y. Nakamura, S.Y. Tsai, The sigma-1 receptor as a pluripotent modulator in living systems. Trends Pharmacol. Sci. 37(4), 262–278 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. C.G. Rousseaux, S.F. Greene, Sigma receptors [σRs]: biology in normal and diseased states. J. Recept. Signal. Transduct. Res. 36(4), 327–388 (2016)

    CAS  PubMed  Google Scholar 

  106. I.S. Zagon, S.R. Goodman, P.J. McLaughlin, Zeta (ζ), the opioid growth factor receptor: identification and characterization of binding subunits. Brain Res. 605(1), 50–56 (1993)

    Article  CAS  PubMed  Google Scholar 

  107. T. Toubia, T. Khalife, The endogenous opioid system: role and dysfunction caused by opioid therapy. Clin. Obstet. Gynecol. 62, 3–10 (2019)

    Article  PubMed  Google Scholar 

  108. A. Koneru, S. Satyanarayana, S. Rizwan, Endogenous opioids: their physiological role and receptors. Global J. Pharmacol. 3(3), 149–153 (2009)

    Google Scholar 

  109. T.A. Koshimizu, K. Honda, S. Nagaoka-Uozumi, A. Ichimura, I. Kimura, M. Nakaya, N. Sakai, K. Shibata, K. Ushijima, A. Fujimura, A. Hirasawa, H. Kurose, G. Tsujimoto, A. Tanoue, Y. Takano, Complex formation between the vasopressin 1b receptor, β-arrestin-2, and the μ-opioid receptor underlies morphine tolerance. Nat. Neurosci. 21(6), 820–833 (2018)

    Article  CAS  PubMed  Google Scholar 

  110. H. Pathan, J. Williams, Basic opioid pharmacology: an update. Br. J. Pain 6(1), 11–16 (2012)

    Article  PubMed  PubMed Central  Google Scholar 

  111. D.S. Goodsell, The molecular perspective: morphine. Stem Cells 23(1), 144–145 (2005)

    Article  PubMed  Google Scholar 

  112. L.A. Chahl, Opioids - mechanisms of action. Exp Clin Pharmacol 19, 63–65 (1996)

    Google Scholar 

  113. L.L. Christrup, Morphine metabolites. Acta Anaesthcsiol. Scand. 41, 116–122 (1997)

    Article  CAS  Google Scholar 

  114. G. Andersen, L. Christrup, P. Sjøgren, Relationships among morphine metabolism, pain and side effects during long-term treatment. J. Pain Symptom Manag. 25(1), 74–91 (2003)

    Article  CAS  Google Scholar 

  115. J. Lötsch, Opioid metabolites. J. Pain Symptom Manag. 29, S10-24 (2005)

    Article  CAS  Google Scholar 

  116. N. Sunagane, T. Ogawa, T. Uruno, K. Kubota, Mechanism of relaxant action of papaverine VI. Sodium ion dependence of its effect on 45Ca-Efflux in Guinea-Pig Taenia Coli. Jpn. J. Pharmacol. 38, 133–139 (1985)

    Article  CAS  PubMed  Google Scholar 

  117. G. Sanfilippo, Contributo sperimentale all'ipotesi della smetilazione della codeine nell'organismo. I . Influenze della dose sull'assuefazione alla codeina. II. Assuefazione alla codeine attenutacon somministrazione prolungata di morphina. Boll. Soc. Ital. Biol. Sper. 24, 723–726 (1948)

  118. D.A. Yee, R.S. Atayee, B.M. Best, J.D. Ma, Observations on the urine metabolic profile of codeine in pain patients. J. Anal. Toxicol. 38(2), 86–91 (2014)

    Article  CAS  PubMed  Google Scholar 

  119. C.H. Mahler, E.D. Stevens, M.L. Trudell, S.P. Nolan, (-)-Thebaine. Acta Cryst. C52, 3193–3195 (1996)

    CAS  Google Scholar 

  120. T.T. Tok, S.J.T. Gowder, Structural and pharmacological properties of alkaloids with special reference to thebaine type alkaloids. Biomed. J. Sci. Tech. Res. 17(3), 12767–12780 (2019)

    Google Scholar 

  121. L. Maat, J.A. Peters, M.A. Prazeres, Diels-alder reaction of thebaine via N-formylnorthebaine with nitroethene; reduction of the nitro group in 7α-nitroethenoisomorphinans (chemistry of opium alkaloids, part XX). Recl. Trav. Chim. Pays-Bas. 104(7–8), 205–208 (2010)

    Article  Google Scholar 

  122. H. Rapoport, P. Sheldrick, The diels-alder reaction with thebaine. thermal rearrangement of some adducts from acetylenic dienophiles. J. Am. Chem. Soc. 85(11), 1636–1642 (1963)

    Article  CAS  Google Scholar 

  123. H.K. Knutsen, J. Alexander, L. Barregard, M. Bignami, B. Bruschweiler, S. Ceccatelli, B. Cottrill, M. Dinovi, L. Edler, B. Grasl-Kraupp, C. Hogstrand, L. Hoogenboom, C.S. Nebbia, I.P. Oswald, A. Petersen, M. Rose, A.-C. Roudot, T. Schwerdtle, G. Vollmer, H. Wallace, D. Benford, G. Calo, A. Dahan, B. Dusemund, P. Mulder, E. Nemeth-Zamborine, D. Arcella, K. Baert, C. Cascio, S. Levorato, M. Schutte, C. Vleminckx, Update of the scientific opinion on opium alkaloids in poppy seeds. EFSA J. 16(5), 5243–5362 (2018)

    Google Scholar 

  124. M.D. Aceto, L.S. Harris, M.E. Abood, K.C. Rice, Stereoselective μ- and δ-opioid receptor-related antinociception and binding with (+)-thebaine. Eur. J. Pharmacol. 365(2–3), 143–147 (1999)

    Article  CAS  PubMed  Google Scholar 

  125. G. Mikus, A.A. Somogyi, F. Bochner, M. Eichelbaum, ThebaineO-demethylation to oripavine: genetic differences between two rat strains. Xenobiotica 21(11), 1501–1509 (1991)

    Article  CAS  PubMed  Google Scholar 

  126. M.P. Gómez-Serranillos, O.M. Palomino, E. Carretero, A. Villar, Analytical study and analgesic activity of oripavine from Papaver somniferum L. Phytother. Res. 12(5), 346–349 (1998)

    Article  Google Scholar 

  127. B.M. El-Haj, H.S. Ali, N.M. Hamoudi, Oripavine as a new marker of opiate product use. Forensic Toxicol. 29(2), 152–158 (2011)

    Article  CAS  Google Scholar 

  128. C.C. Hodges, J.S. Horn, H. Rapoport, Morphinan alkaloids in Papaver bracteatum: Biosynthesis and Fate. Technical Information Division, Lawrence Berkeley National Laboratory, Berkeley No. 94720 (1977)

  129. H. Kodaira, S. Spector, Transformation of thebaine to oripavine, codeine, and morphine by rat liver, kidney, and brain microsomes. Proc. Natl. Acad. Sci. USA 85(4), 1267–1271 (1988)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. H. Uprety, D.S. Bhakuni, R.S. Kapil, Biosynthesis of Papaverine. Phytochemistry 14, 1535–1537 (1975)

    Article  CAS  Google Scholar 

  131. A.V. Lakyanov, V.S. Onoprienko, V.A. Zasosov, Industrial Methods of Preparing Papaverine (A Review of the Literature) (Chemical and Pharmaceutical Scientific-Research Institute, Moscow, 1972).

    Book  Google Scholar 

  132. S.K. Talapatra, B. Talapatra, Chemistry of Plant Natural Products: Stereochemistry, Conformation, Synthesis, Biology, and Medicine (Spring, Heidelberg New York Dordrecht London, 2015).

    Book  Google Scholar 

  133. C. Hanna, J. Shutt, Papaverine analogs. VI relationship between chemical structure and coronary vasodilator action. Arch. Exp. Pathol. U. Pharmakol. 220, S43-51 (1953)

    Google Scholar 

  134. A. Capasso, S. Piacente, N. Tommasi, L. Rastrelli, C. Pizza, The effect of isoquinoline alkaloids on opiate withdrawal. Curr. Med. Chem. 13(7), 807–812 (2006)

    Article  CAS  PubMed  Google Scholar 

  135. L. Hertle, H. Nawrath, Effects of papaverine on human isolated bladder muscle. Urol. Res. 18, 227–231 (1990)

    Article  CAS  PubMed  Google Scholar 

  136. N. Sunagane, T. Uruno, K. Kubota, Mechanism of relaxant action of papaverine, effect on caffeine-induced contraction of guinea pig taenia coli. Jpn. J. Pharmacol. 32(5), 785–793 (1982)

    Article  CAS  PubMed  Google Scholar 

  137. J.P. Rosazza, M. Kammer, L. Youel, Microbial models of mammalian metabolism O-demethylations of papaverine. Xenobiotica 7, 133–143 (1977)

    Article  CAS  PubMed  Google Scholar 

  138. J. Axelrod, J. Cochin, The inhibitory action of nalorphine on the enzymatic N-demethylation of narcotic drugs. J. Pharmacol. Exp. Ther. 121(1), 107–112 (1957)

    CAS  PubMed  Google Scholar 

  139. F.M. Belpaire, M.G. Bogaert, M.T. Rosseel, Metabolism of papaverine I. Identification of metabolites in rat bile. Xenobiotica 5, 413–420 (1975)

    Article  CAS  PubMed  Google Scholar 

  140. F.M. Belpaire, M.T. Rosseel, M.G. Bogaert, Metabolism of papaverine IV. Urinary elimination of papaverine metabolites in man. Xenobiotica 8, 297–300 (1978)

    Article  CAS  PubMed  Google Scholar 

  141. G. Wilen, P. Ylitalo, Metabolism of [14C] papaverine in man. J. Pharm. Pharmacol. 34, 264–266 (1982)

    Article  CAS  PubMed  Google Scholar 

  142. J.C. Davila, C.G. Reddy, P.J. Davis, D. Acosta, Toxicity assessment of paraverine hydrochloride and papaverine-derived metabolites in primary cultures of rat hepatocytes. In Vitro Cell Dev. Biol. 26(5), 515–524 (1990)

    Article  CAS  PubMed  Google Scholar 

  143. M.A. Al-Yahya, M.M.A. Hassan, Noscapine. Anal. Profiles Drug Subst. 11, 407–461 (1982)

    Article  CAS  Google Scholar 

  144. S. Cheriyamundath, T. Mahaddalkar, P.K. Reddy Nagireddy, B. Sridhar, S. Kantevari, M. Lopus, Insights into the structure and tubulin-targeted anticancer potential of N-(3-bromobenzyl) noscapine. Pharmacol. Rep. 1, 48–53 (2019)

    Article  CAS  Google Scholar 

  145. M. Tripathi, P.L. Reddy, D.S. Rawat, Noscapine and its analogues as anti-cancer agents. Chem. Biol. Interface 4, 1–22 (2014)

    Google Scholar 

  146. N. Dhiman, A. Sood, A. Sharma, Noscapine: an anti-mitotic agent. World J. Pharm. Pharm. Sci. 3, 324–338 (2013)

    Google Scholar 

  147. K. Ye, Y. Ke, N. Keshava, J. Shanks, J.A. Kapp, R.R. Tekmal, J. Petros, H.C. Joshi, Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells. Proc. Natl. Acad. Sci. USA 95, 1601–1606 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. L. Richards, A. Lutz, D.K. Chalmers, A. Jarrold, T. Bowser, G.W. Stevens, S.L. Gras, Production of metabolites of the anti-cancer drug noscapine using a P450BM3 mutant library. Biotechnol. Rep. 24, e00372 (2019)

    Article  Google Scholar 

  149. N. Tsunoda, Metabolic fate of noscapine.11.Isolation and identification of novel metabolites produce4 by C-C bond cleavage. Xenobiotica 9, 181–187 (1979)

    Article  CAS  PubMed  Google Scholar 

  150. A.O. Alnajjar, M.E. El-Zaria, Synthesis and characterization of novel azo-morphine derivatives for possible use in abused drugs analysis. Eur. J. Med. Chem. 43, 357–363 (2008)

    Article  CAS  PubMed  Google Scholar 

  151. D.A. Rincón, M.N.D.S. Cordeiro, R.A. Mosquera, Theoretical study of morphine and heroin: conformational study in gas phase and aqueous solution and electron distribution analysis. Int. J. Quantum Chem. 110, 2472–2482 (2010)

    Google Scholar 

  152. J.J. Rady, G.I. Elmer, G.M. Fujimoto, Opioid receptor selectivity of heroin given intracerebroventricularly differs in six strains of inbred mice. J. Pharmacol. Exp. Ther. 288, 438–445 (1999)

    CAS  PubMed  Google Scholar 

  153. J.J. Rady, F. Aksu, J.M. Fujimoto, The heroin metabolite, 6-monoacetylmorphine, activates delta opioid receptors to produce antinociception in Swiss-Webster mice. J. Pharmacol. Exp. Ther. 268(3), 1222–1231 (1994)

    CAS  PubMed  Google Scholar 

  154. D.E. Selley, C.C. Cao, T. Sexton, J.A. Schwegel, T.J. Martin, S.R. Childers, mu Opioid receptor-mediated G-protein activation by heroin metabolites: evidence for greater efficacy of 6-monoacetylmorphine compared with morphine. Biochem. Pharmacol. 62(4), 447–455 (2001)

    Article  CAS  PubMed  Google Scholar 

  155. H.H. Maurer, C. Sauer, D.S. Theobald, Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine. Lippincott Williams Wilkins 28, 447–453 (2006)

    CAS  Google Scholar 

  156. A. Murray, N.A. Hagen, Hydromorphone. J. Pain Symptom Manag. 29, S57–S66 (2005)

    Article  CAS  Google Scholar 

  157. N.H. Barakat, R.S. Atayee, M.B. Best, J.D. Ma, Urinary hydrocodone and metabolite distributions in pain patients. J. Anal. Toxicol. 38, 404–409 (2014)

    Article  CAS  PubMed  Google Scholar 

  158. S. Valtier, V.S. Bebarta, Excretion profile of hydrocodone, hydromorphone and norhydrocodone in urine following single dose administration of hydrocodone to healthy volunteers. J. Anal. Toxicol. 36, 507–514 (2012)

    Article  CAS  PubMed  Google Scholar 

  159. P. Gulur, K. Koury, P. Arnstein, H. Lee, P. McCarthy, C. Coley, E. Mort, Morphine versus hydromorphone: does choice of opioid influence outcomes? Pain Res. Treat. 2015, 1–6 (2015)

    Article  Google Scholar 

  160. B. Lalovic, E. Kharasch, C. Hoffer, L. Risler, L. Liuchen, D. Shen, Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin. Pharmacol. Ther. 79(5), 461–479 (2006)

    Article  CAS  PubMed  Google Scholar 

  161. M. Kokki, M. Heikkinen, P. Välitalo, H. Hautajärvi, J. Hokkanen, H. Pitkänen, U. Sankilampi, V.-P. Ranta, H. Kokki, Maturation of oxycodone pharmacokinetics in neonates and infants: oxycodone and its metabolites in plasma and urine. Br. J. Clin. Pharm. 83(4), 791–800 (2016)

    Article  CAS  Google Scholar 

  162. A.Z. DePriest, R. Heltsley, D.L. Black, J.M. Mitchell, C. LoDico, R. Flegel, E.J. Cone, Prescription opioids. V. Metabolism and excretion of oxymorphone in urine following controlled single dose administration. J. Anal. Toxicol. 40(8), 566–574 (2016)

    Article  CAS  PubMed  Google Scholar 

  163. H.S. Smith, Clinical pharmacology of oxymorphone. Pain Med. 10, S3–S10 (2009)

    Article  Google Scholar 

  164. D.S. Craig, Oxymorphone extended-release tablets (Opana ER) for the management of chronic pain. P T 35(6), 324–329 (2010)

    PubMed  PubMed Central  Google Scholar 

  165. S.M. Fishman, B. Wilsey, G. Mahajan, P. Molina, Methadone reincarnated: novel clinical applications with related concerns. Pain Med. 3, 339–348 (2002)

    Article  PubMed  Google Scholar 

  166. P. Lisberg, F. Scheinmann, Is it time to consider use of levo-methadone (R-(-)-Methadone) to replace racemic methadone? J. Dev. Drugs. 2, 1–2 (2013)

    Google Scholar 

  167. N. Ansermot, Substitution of (R, S)-methadone by (R)-methadone. Arch. Intern. Med. 170(6), 529–536 (2010)

    Article  CAS  PubMed  Google Scholar 

  168. D.A.N. Silverman, R.T. Nettleton, K.B. Spencer, M. Wallisch, G.D. Olsen, S-Methadone augments R-methadone induced respiratory depression in the neonatal guinea pig. Respir. Physiol. Neurobiol. 169(3), 252–261 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. E.F. Mccance-Katz, (R)-methadone versus racemic methadone: what is best for patient care? Addiction 106(4), 687–688 (2011)

    Article  PubMed  PubMed Central  Google Scholar 

  170. J. Gaertner, R. Voltz, C. Ostgathe, Methadone: a closer look at the controversy. J. Pain Symptom Manage. 36(2), e4–e7 (2008)

    Article  PubMed  Google Scholar 

  171. S. Gadel, C. Friedel, E.D. Kharasch, Differences in methadone metabolism by CYP2B6 variants. Drug Metab. Dispos. 43(7), 994–1001 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. M.E.M. Larson, T.M. Richards, Quantification of a methadone metabolite (EDDP) in urine: assessment of compliance. Clin. Med. Res. 7(4), 134–141 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. K.L. Preston, D.H. Epstein, D. Davoudzadeh, M.A. Huestis, Methadone and metabolite urine concentrations in patients maintained on methadone. J. Anal. Toxicol. 27(6), 332–341 (2003)

    Article  CAS  PubMed  Google Scholar 

  174. Tramadol Update Review Report, 36th ECDD, (2014)

  175. M. Subedi, S. Bajaj, M.S. Kumar, Y.C. Mayur, An overview of tramadol and its usage in pain management and future perspective. Biomed. Pharmacother. 111, 443–451 (2019)

    Article  CAS  PubMed  Google Scholar 

  176. Q. Shen, Y. Qian, X. Xu, W. Li, J. Liu, W. Fu, Design, synthesis and biological evaluation of N-phenylalkyl-substituted tramadol derivatives as novel μ opioid receptor ligands. Acta Pharmacol. Sin. 36(7), 887–894 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. J. Marcotte, Formal Synthesis of (+/-) Morphine via an Oxy-cope/Claisen/Ene Reaction Cascade. PhD Dissertation, The University of Ottawa, (2012)

  178. D.F. Taber, T.D. Neubert, M.F. Schlecht, in Strategies and Tactics in Organic Synthesis, Chap. 11, vol. 5, ed. by M. Harmata (Elsevier, Amsterdam, 2004), pp. 353–389

  179. L.M. Mascavage, M.L. Wilson, D.R. Dalton, Syntheses of morphine and codeine (1992–2002), templates for exploration of synthetic tools. Curr. Org. Synth. 3, 99–120 (2006)

    Article  CAS  Google Scholar 

  180. K.A. Parker, D. Fokas, Convergent synthesis of (.+-.)-dihydroisocodeine in 11 steps by the tandem radical cyclization strategy, a formal total synthesis of (.+-.)-morphine. J. Am. Chem. Soc. 114(24), 9688–9689 (1992)

    Article  CAS  Google Scholar 

  181. J.D. White, P. Hmciar, F. Stappenbeck, Asymmetric synthesis of (+)-morphine. The phenanthrene route revisited. J. Org. Chem. 62, 5250–5251 (1997)

    Article  CAS  Google Scholar 

  182. D. Trauner, J.W. Bats, A. Werner, J. Mulzer, Synthesis of enantiomerically pure morphine alkaloids: the hydrophenanthrene route. J. Org. Chem. 63, 5908–5918 (1998)

    Article  CAS  PubMed  Google Scholar 

  183. Q. Li, H. Zhang, Total synthesis of codeine. Chem-Eur J. 21(46), 16379–16382 (2015)

    Article  CAS  PubMed  Google Scholar 

  184. D.F. Taber, T.D. Neubert, A. Rheingold, Synthesis of (-)-morphine. J. Am. Chem. Soc. 124, 12416–12417 (2002)

    Article  CAS  PubMed  Google Scholar 

  185. A.T. Omori, K.J. Finn, H. Leisch, R.J. Carroll, T. Hudlicky, Chemoenzymatic total synthesis of (+)-codeine by sequential intramolecular Heck cyclizations via C-B–D ring construction. Synlett 18, 2859–2862 (2007)

    Google Scholar 

  186. G. Stork, A. Yamashita, J. Adams, G.R. Schulte, R. Chesworth, Y. Miyazaki, J.J. Farmer, Regiospecific and stereoselective syntheses of (+/-) morphine, codeine, and thebaine via a highly stereocontrolled intramolecular 4 + 2 cycloaddition leading to a phenanthrofuran system. J. Am. Chem. Soc. 131(32), 11402–11406 (2009)

    Article  CAS  PubMed  Google Scholar 

  187. P. Magnus, N. Sane, B.P. Fauber, V. Lynch, Concise syntheses of (−)-galanthamine and (±)-codeine via intramolecular alkylation of a phenol derivative. J. Am. Chem. Soc. 131(44), 16045–16047 (2009)

    Article  CAS  PubMed  Google Scholar 

  188. H. Koizumi, S. Yokoshima, T. Fukuyama, Total synthesis of (−)-morphine. Chem. Asian J. 5(10), 2192–2198 (2010)

    Article  CAS  PubMed  Google Scholar 

  189. M. Tissot, R.J. Phipps, C. Lucas, R.M. Leon, R.D.M. Pace, T. Ngouansavanh, M.J. Gaunt, Gram-scale enantioselective formal synthesis of morphine through anortho-paraoxidative phenolic coupling strategy. Angew. Chem. 53(49), 13498–13501 (2014)

    Article  CAS  Google Scholar 

  190. S. Chu, N. Münster, T. Balan, M.D. Smith, A Cascade strategy enables a total synthesis of (±)-morphine. Angew. Chem. 55(46), 14306–14309 (2016)

    Article  CAS  Google Scholar 

  191. H. Umihara, S. Yokoshima, M. Inoue, T. Fukuyama, Total synthesis of (−)-morphine. Chem. Eur. J. 23(29), 6993–6995 (2017)

    Article  CAS  PubMed  Google Scholar 

  192. J. Rautschek, A. Jäger, P. Metz, Formal synthesis of (−)-codeine by application of temporary Thio derivatization. Org. Lett. 20(3), 832–835 (2018)

    Article  CAS  PubMed  Google Scholar 

  193. Q. Zhang, F.-M. Zhang, C.-S. Zhang, S.-Z. Liu, J.-M. Tian, S.-H. Wang, X.-M. Zhang, Y.-Q. Tu, Enantioselective synthesis of cis-hydrobenzofurans bearing all-carbon quaternary stereocenters and application to total synthesis of (-)-morphine. Nat. Commun. 10(1), 1–7 (2019)

    CAS  Google Scholar 

  194. J. Brousseau, A. Xolin, L. Barriault, A nine-step formal synthesis of (±)-morphine. Org. Lett. 21(5), 1347–1349 (2019)

    Article  CAS  PubMed  Google Scholar 

  195. H. Rapoport, C.H. Lovell, H.R. Reist, M.E. Warren, The synthesis of thebaine and northebaine from codeinone dimethyl ketal. J. Am. Chem. Soc. 89(8), 1942–1947 (1967)

    Article  CAS  PubMed  Google Scholar 

  196. I. Seki, Studies on the morphine alkaloids and its related compounds. XVII. One-step preparations of enol ether and pyrrolidinyl dienamine of normorphinone derivatives. Chem. Pharm. Bull. 18(4), 671–676 (1970)

    Article  CAS  Google Scholar 

  197. A. Coop, K.C. Rice, A novel synthesis of thebaine from codeine. Heterocycles 49, 43–47 (1998)

    Article  CAS  Google Scholar 

  198. R.D. Singera, P.J. Scammellsb, Alternative methods for the MnO2 oxidation of codeine methylether to thebaine utilizing ionic liquids. Tetrahedron Lett. 42, 6831–6833 (2001)

    Article  Google Scholar 

  199. S. Hosztafi, Recent advances in the chemistry of oripavine and its derivatives. ABB 5, 704–717 (2014)

    Article  CAS  Google Scholar 

  200. M. Geffe, T. Opatz, Enantioselective synthesis of (−)-dihydrocodeine and formal synthesis of (−)-thebaine, (−)-codeine, and (−)-morphine from a deprotonated α-aminonitrile. Org. Lett. 16, 5282–5285 (2014)

    Article  CAS  PubMed  Google Scholar 

  201. P. Koukal, J. Hajicek, S. Gupta, T. Hudlicky, Model studies toward the total synthesis of thebaine by an intramolecular cycloaddition strategy. ChemistrySelect 2(26), 7783–7786 (2017)

    Article  CAS  Google Scholar 

  202. D.A. Guthrie, A.W. Frank, C.B. Purves, Studies in the polyoxyphenol series IX, the synthesis of papaverine and papaveraldine by the Pomeranz-Fritsch method. Can. J. Chem. 33, 729–742 (1955)

    Article  CAS  Google Scholar 

  203. G. Wu, A.L. Rhiengold, S.J. Geib, R.F. Heck, Palladium-catalyzed annulation of aryl iodides with diphenylacetylene. Organometallics 1987, 6 (1941)

    Google Scholar 

  204. K.R. Roesch, R.C. Larock, Synthesis of isoquinolines and pyridines by the palladium/copper-catalyzed coupling and cyclization of terminal acetylenes and unsaturated imines: the total synthesis of decumbenine B. J. Org. Chem. 67(1), 86–94 (2002)

    Article  CAS  PubMed  Google Scholar 

  205. R.P. Korivi, C.-H. Cheng, Highly efficient synthesis of isoquinolines via nickel-catalyzed annulation of 2-iodobenzaldimines with alkynes: evidence for dual pathways of alkyne insertion. Org. Lett. 7(23), 5179–5182 (2005)

    Article  CAS  PubMed  Google Scholar 

  206. S. Zhang, D. Huang, G. Xu, S. Cao, R. Wang, S. Peng, J. Sun, An efficient synthesis of isoquinolines via rhodium-catalyzed direct C-H functionalization of arylhydrazines. Org. Biomol. Chem. 13(29), 7920–7923 (2015)

    Article  CAS  PubMed  Google Scholar 

  207. C.D. Gilmore, K.M. Allan, B.M. Stoltz, Orthogonal synthesis of indolines and isoquinolines via aryne annulation. J. Am. Chem. Soc. 130, 1558–1559 (2008)

    Article  CAS  PubMed  Google Scholar 

  208. M.V. Madhubabu, R. Shankara, R. Akulaa, U.K. Syam Kumar, M.V.B. Rao, Facile synthesis of papaverine, (±) setigeridine, (±) setigerine, and related isoquinoline alkaloids. Der. Pharma. Chem. 6(4), 50–56 (2014)

    CAS  Google Scholar 

  209. P.E. Ghaly, R.M. Abou El-Magd, C.D.M. Churchill, J.M. Tuszynski, F.G. West, A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation. Oncotarget 7, 40518–40530 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  210. D.U. Lee, (-)-β-Narcotine: a facile synthesis and the degradation with ethyl chloroformate. Bull. Korean Chem. Soc. 23(11), 1548–1552 (2002)

    Article  CAS  Google Scholar 

  211. M.D.P.C. Soriano, N. Shankaraiah, L.S. Santos, Short synthesis of noscapine, bicuculline, egenine, capnoidine, and corytensine alkaloids through the addition of 1-siloxy-isobenzofurans to imines. Tetrahedron Lett. 51, 1770–1773 (2010)

    Article  CAS  Google Scholar 

  212. A.J. Debono, S.J. Mistry, J. Xie, D. Muthiah, J. Phillips, S. Ventura, R. Callaghan, C.W. Pouton, B. Capuano, P.J. Scammells, The synthesis and biological evaluation of multifunctionalised derivatives of noscapine as cytotoxic agents. Chem. Med. Chem. 9, 399–410 (2014)

    Article  CAS  PubMed  Google Scholar 

  213. R. Tomar, A. Sahni, I. Chandra, V. Tomar, R. Chandra, Review of noscapine and its analogues as potential anti-cancer drugs. Mini Rev. Org. Chem. 15, 1–20 (2018)

    Article  Google Scholar 

  214. A.J. Debono, J.H. Xie, S. Ventura, C.W. Pouton, B. Capuano, P.J. Scammells, Synthesis and biological evaluation of N-substituted noscapine analogues. Chem. Med. Chem. 7, 2122–2133 (2012)

    Article  CAS  PubMed  Google Scholar 

  215. K.B. Mishra, R.C. Mishra, V.K. Tiwari, First noscapine glycoconjugates inspired by click chemistry. RSC Adv. 5(64), 51779–51789 (2015)

    Article  CAS  Google Scholar 

  216. A.K. Verma, S. Bansal, J. Singh, R.K. Tiwari, V. Kasi Sankar, V. Tandon, R. Chandra, Synthesis and in vitro cytotoxicity of haloderivatives of noscapine. Bioorganic Med. Chem. 14, 6733–6736 (2006)

    Article  CAS  Google Scholar 

  217. R. Aneja, S.N. Vangapandu, M. Lopus, V.G. Viswesarappa, N. Dhiman, A. Verma, C. Chandra, D. Panda, H.C. Joshi, Synthesis of microtubule-interfering halogenated noscapine analogs that perturb mitosis in cancer cells followed by cell death. Biochem. Pharmacol. 72, 415–426 (2006)

    Article  CAS  PubMed  Google Scholar 

  218. R.C. Mishra, P. Karna, S.R. Gundala, V. Pannu, R.A. Stanton, K.K. Gupta, M.H. Robinson, M.O. Lopus, L. Wilson, M. Henary, R. Aneja, Second generation benzofuranone ring substituted noscapine analogs: synthesis and biological evaluation. Biochem. Pharmacol. 82, 110–121 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. R.C. Mishra, S.R. Gundala, P. Karna, M. Lopus, K.K. Gupta, M. Nagaraju, D. Hamelberg, V. Tandon, D. Panda, M.D. Reid, R. Aneja, Design, synthesis and biological evaluation of di-substituted noscapine analogs as potent and microtubule-targeted anticancer agents. Bioorg. Med. Chem. Lett. 25(10), 2133–2140 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. S.M. Devine, C. Yong, D. Amenuvegbe, L. Aurelio, D. Muthiah, C.W. Pouton, R. Callaghan, B. Capuano, P.J. Scammells, Synthesis and pharmacological evaluation of noscapine inspired 5-substituted tetrahydroisoquinolines as cytotoxic agents. J. Med. Chem. 61, 8444–8456 (2018)

    Article  CAS  PubMed  Google Scholar 

  221. M. Mohebbi, M. Bararjanian, S.N. Ebrahimi, M. Smieško, P. Salehi, Noscapine derivatives as new chiral catalysts in asymmetric synthesis: highly enantioselective addition of diethylzinc to aldehydes. Synthesis 50, 1841–1848 (2018)

    Article  CAS  Google Scholar 

  222. I. Iijima, J. Minamikawa, A.E. Jacobson, A.E. Jacobson, K.C. Rice, Studies in the (+)-morphinan series, 4. A markedly improved synthesis of (+)-morphine. J. Org. Chem. 43(7), 1462–1463 (1978)

    Article  CAS  Google Scholar 

  223. C.R.A. Wright, On the action of organic acids and their anhydrides on the natural alkaloids. J. Chem. Soc. 27, 1031–1043 (1847)

    Article  Google Scholar 

  224. L.R. Odell, J. Skopec, A. McCluskey, A ‘cold synthesis’ of heroin and implications in heroin signature analysis Utility of trifluoroacetic/acetic anhydride in the acetylation of morphine. Forensic Sci. Int. 164, 221–229 (2006)

    Article  CAS  PubMed  Google Scholar 

  225. C.C. Clark, A study of procedures for the identification of heroin. J. Forensic Sci. 22, 418–428 (1977)

    Article  CAS  PubMed  Google Scholar 

  226. J. Schwyzer, Die Fabrikation Pharmazeutisher Und Chemisch-Technischer Produkte (Verlag von Julius Springer, Berlin, 1931), p. 364

    Google Scholar 

  227. P.A. Hays, G.S. Remaud, E. Jamin, Y.L. Martin, Geographic origin determination of heroin and cocaine using site-specific isotopic ratio deuterium NMR. J. Forensic Sci. 45, 552–562 (2000)

    Article  CAS  PubMed  Google Scholar 

  228. S. Klemenc, 4-Dimethylaminopyridine as a catalyst in heroin synthesis. Forensic Sci. Int. 129, 194–199 (2002)

    Article  CAS  PubMed  Google Scholar 

  229. T.S. Bailey, P.S. Gee, R. Rezaie, Process for the synthesis of hydromorphone. US WO2006005112A1, PCT/AU2005/001002 (2006)

  230. R. Vardanyan, V. Hruby, Synthesis of Essential Drugs (Elsevier, Amsterdam, 2006), p. 25

    Google Scholar 

  231. M.T. Long, A.M. Hailes, G.W. Kirby, N.C. Bruce, Transformations of morphine alkaloids by Pseudomonas putida M10. Appl. Environ. Microbiol. 61, 3645 (1995)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. R. Csuk, G. Vasileva, A. Barthel, Towards an efficient preparation of hydromorphone. Synthesis 44(18), 2840–2842 (2012)

    Article  CAS  Google Scholar 

  233. B. Murphy, I. Šnajdr, A. Machara, M.A.A. Endoma-Arias, T.C. Stamatatos, D.P. Cox, T. Hudlický, Conversion of thebaine to oripavine and other useful intermediates for the semisynthesis of opiate-derived agents: synthesis of hydromorphone. Adv. Synth. Catal. 356, 2679–2687 (2014)

    Article  CAS  Google Scholar 

  234. L. Rycek, J.J. Hayward, M.A. Latif, J. Tanko, R. Simionescu, T. Hudlicky, Chemoenzymatic total synthesis of hydromorphone by an oxidative dearomatization/intramolecular [4 + 2] cycloaddition sequence: a second-generation approach. J. Org. Chem. 81, 10930–10941 (2016)

    Article  CAS  PubMed  Google Scholar 

  235. V. Varghese, T. Hudlicky, Short chemoenzymatic total synthesis ofent-hydromorphone: an oxidative dearomatization/intramolecular [4+2] cycloaddition/amination sequence. Angew. Chem. 53(17), 4355–4358 (2014)

    Article  CAS  Google Scholar 

  236. S.A. Chambers, J.M. DeSousa, E.D. Huseman, S.D. Townsend, The DARK side of total synthesis: strategies and tactics in psychoactive drug production. ACS Chem. Neurosci. 9, 2307–2330 (2018)

    Article  CAS  PubMed  Google Scholar 

  237. T.H. Black, J.C. Forsee, D.A. Probst, A rapid, nearly quantitative conversion of codeine to hydrocodone. Synth. Commun. 30(17), 3195–3201 (2000)

    Article  CAS  Google Scholar 

  238. R.J. Carroll, H. Leisch, L. Rochon, T. Hudlicky, D.P. Cox, One-pot conversion of thebaine to hydrocodone and synthesis of neopinone ketal. J. Org. Chem. 74, 747–752 (2009)

    Article  CAS  PubMed  Google Scholar 

  239. T. Hudlicky, V. Varghese, Total synthesis of dihydrocodeine and hydrocodone via a double claisen rearrangement and C-10/C-11 closure strategy. Synlett 24(03), 369–374 (2013)

    Article  CAS  Google Scholar 

  240. A.B. Gomez, P. Holmberg, J.E. Backvall, B. Martin-Matute, Transition metal-catalyzed redox isomerization of codeine and morphine in water. RSC Adv. 4, 39519–39522 (2014)

    Article  CAS  Google Scholar 

  241. R. Krassnig, C. Hederer, H. Schmidhamme, Optimization of the synthesis of oxycodone and 5-methyloxycodonearch. Pharm. Phan. Med. Chem. 329, 325–326 (1996)

    Article  CAS  Google Scholar 

  242. G.B. Kok, P.J. Scammells, Improved synthesis of 14-hydroxy opioid pharmaceuticals and intermediates. RSC Adv. 2, 11318–11325 (2012)

    Article  CAS  Google Scholar 

  243. A. Kimishima, H. Umihara, A. Mizoguchi, S. Yokoshima, T. Fukuyama, Synthesis of (−)-oxycodone. Org. Lett. 16(23), 6244–6247 (2014)

    Article  CAS  PubMed  Google Scholar 

  244. T. Hudlicky, M.A. Endoma-Arias, M. Makarova, H. Dela Paz, Chemoenzymatic total synthesis of (+)-oxycodone from phenethyl acetate. Synthesis 51, 225–232 (2018)

    Google Scholar 

  245. A. Lipp, M. Selt, D. Ferenc, D. Schollmeyer, R. Waldvogel, T. Opatz, Synthesis of (–)-oxycodone. Org. Lett. 21, 1828–1831 (2019)

    Article  CAS  PubMed  Google Scholar 

  246. G.I.L. Kang, Synthesis and Applications of Deuterated Methadone and Metabolites to Biotransformation and Disposition Studies. Ph.D. Dissertation, University of British Columbia (1981)

  247. C.J. Barnett, J.C. Smirz, Stereochemistry of bockmuhl’s synthesis of methadone. J. Org. Chem. 41, 710–711 (1976)

    Article  CAS  PubMed  Google Scholar 

  248. A.H. Beckett, N.J. Harper, 162. ConfzgurationaE studies in synthetic analgesics: the synthesis of (-)-methadone from D-( -)-ahnine. J. Chem. Soc. 0(0), 858–861 (1957)

    Article  CAS  Google Scholar 

  249. D.L. Hachey, M.J. Kreek, D.H. Mattson, Quantitative analysis of methadone in biological fluids using deuterium-labeled methadone and GLC-chemical-ionization mass spectrometry. J. Pharm. Sci. 66, 1579–1589 (1977)

    Article  CAS  PubMed  Google Scholar 

  250. G.I.L. Kang, F.S. Abbotts, R. Burton, Synthesis and Mass Spectrometry of Deuterated Methadone and Methadone Metabolites. Biomed. Mas. Spectrom. 6, 179–186 (1979)

    Article  CAS  Google Scholar 

  251. B.M. Gérardy, J. Poupaert, P. Dumont, An efficient synthesis of the enantiomers of methadone-D10. Bull. Soc. Chim. Belg. 90(9), 977–980 (2010)

    Article  Google Scholar 

  252. C. Alvarado, A. Guzman, E. Diaz, R. Patino, Synthesis of Tramadol and Analogous. J. Mex. Chem. Soc. 49(4), 324–327 (2005)

    CAS  Google Scholar 

  253. F. Lecerf-Schmidt, R. Haudecoeur, B. Peres, M.M.F. Queiroz, L. Marcourt, S. Challal, E.F. Queiroz, G.S. Taiwe, T. Lomberget, M.L. Borgne, J.L. Wolfender, M.D. Waard, R.J. Robinsg, A. Boumendjel, Biomimetic synthesis of Tramadol. Chem. Commun. 51(77), 14451–14453 (2015)

    Article  CAS  Google Scholar 

  254. S. Sonavane, R. Walavalkar, N. Pradhan, Comparative performance evaluation & systematic screening of 2-Methf as green solvent for cost effective, improved industrial production of tramadol hydrochloride. IJDR 7, 15890–15894 (2017)

    Google Scholar 

  255. G.A.W. Beaudoin, P.J. Facchini, Benzylisoquinoline alkaloid biosynthesis in opium poppy. Planta 240(1), 19–32 (2014)

    Article  CAS  PubMed  Google Scholar 

  256. M. Dastmalchi, M.R. Park, J.S. Morris, P. Facchini, Family portraits: the enzymes behind benzylisoquinoline alkaloid diversity. Phytochem. Rev. 17(2), 249–277 (2017)

    Article  CAS  Google Scholar 

  257. J. Ziegler, P.J. Facchini, R. Geißler, J. Schmidt, C. Ammera, R. Kramell, S. Voigtländer, A. Gesell, S. Pienkny, W. Brandt, Evolution of morphine biosynthesis in opium poppy. Phytochemistry 70, 1696–1707 (2009)

    Article  CAS  PubMed  Google Scholar 

  258. Y. Alagoz, T. Gurkok, B. Zhang, T. Unver, Manipulating the biosynthesis of bioactive compound alkaloids for next-generation metabolic engineering in opium poppy using CRISPR-Cas 9 genome editing technology. Sci. Rep. 6(1), 30910 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. A. Onoyovwe, J.M. Hagel, X. Chen, M.F. Khan, D.C. Schriemer, P.J. Facchini, Morphine biosynthesis in opium poppy involves two cell types: sieve elements and laticifers. Plant Cell 25(10), 4110–4122 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. X. Chen, J.M. Hagel, L. Chang, J.E. Tucker, S. Shiigi, Y. Yelpaala, H.Y. Chen, R. Estrada, J. Colbeck, M. Enquist-Newman, A.B. Ibáñez, G. Cottarel, G.M. Vidanes, P.J. Facchini, A pathogenesis-related 10 protein catalyzes the final step in thebaine biosynthesis. Nat. Chem. Biol. 14(7), 738–743 (2018)

    Article  CAS  PubMed  Google Scholar 

  261. F.R. Stermitz, H. Rapoport, The biosynthesis of opium alkaloids, alkaloid interconversions in papaver somniferum and P. orientale. J. Am. Chem. Soc. 83, 4045–4050 (1961)

    Article  CAS  Google Scholar 

  262. S. Pathak, D. Lakhwani, P. Gupta, B.K. Mishra, S. Shukla, M.H. Asif, P.K. Trivedi, Comparative transcriptome analysis using high papaverine mutant of papaver somniferum reveals pathway and uncharacterized steps of papaverine biosynthesis. PLoS ONE 8(5), e65622 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. B.H. Novak, T. Hudlicky, J.W. Reed, J. Mulzer, D. Trauner, Morphine synthesis and biosynthesis-an update. Curr. Org. Synth. 4, 343–362 (2000)

    CAS  Google Scholar 

  264. S. Pienkny, W. Brandt, J. Schmidt, R. Kramell, J. Ziegler, Functional characterization of a novel benzylisoquinoline O-methyltransferase suggests its involvement in papaverine biosynthesis in opium poppy (Papaversomniferum L). Plant J. 60, 56–67 (2009)

    Article  CAS  PubMed  Google Scholar 

  265. Y. Li, C.D. Smolke, Engineering biosynthesis of the anticancer alkaloid noscapine in yeast. Nat. Commun. 7, 12137–12151 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Y. Li, S. Li, K. Thodey, I. Trenchard, A. Cravens, C.D. Smolke, Complete biosynthesis of noscapine and halogenated alkaloids in yeast. Proc. Natl. Acad. Sci. 115(17), E3922–E3931 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Kaboudin, B., Sohrabi, M. Chemistry and synthesis of major opium alkaloids: a comprehensive review. J IRAN CHEM SOC 18, 3177–3218 (2021). https://doi.org/10.1007/s13738-021-02268-y

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