Papaver somniferum Morphinan alkaloids

HUANG, F.-C., KUTCHAN, T.M., Distribution of morphinan and benzo[c]phenanthridine alkaloid gene transcript accumulation in Papaver somniferum, Phytochemistry, 2000,53, 555-564. 

Biotransformations of morphinan alkaloids have been reported for plant, fungal, and mammalian enzymatic systems with emphasis on rather specific reactions such as the reduction of ketones, N- and O-demethylation, and perox-idative transformations. Furuya et al. used immobilized tissue culture cells of Papaver somniferum to accomplish the selective reduction of codeinone (135) to codeine (136) (207) (Scheme 30). Suspension cultures of a well-established cell line of P. somniferum were grown for one week as a source of cell mass for immobilization in calcium alginate. The cells continued to live in the alginate matrix for 6 months maintaining their biological activity. The reduction of co-... 

Morphine (10) and codeine (11), constituents of opium, are the most interesting alkaloids found in nature. Morphine is also the oldest alkaloid isolated, in 1805, by the German pharmacist Sertiimer from opium, the sun dried latex of Papaver somniferum. The structure of morphine with its so-called morphinan skeleton, once called the acrobat under the alkaloids, was finally elucidated in 1952 by the first total synthesis performed by Gates and Tschudi. Many syntheses would follow [26], but all morphine used today, whether legal or illicit, originates in the natural source P. somniferum or its extract, opium. The latex may contain up to 20% morphine. Most legal morphine is converted into the anticough medicine codeine (Table 5.1) by treatment with trimethylanilinium methoxide, whereas almost all illicit morphine is acetylated to the diacetate heroin. 

Conversion of (S)-reticuline to its ( )-epimer is the first committed step in morphinan alkaloid biosynthesis in certain species. 1,2-Dehydroreticuline reductase catalyzes the stereospecific reduction of 1,2-dehydroreticuline to (7 )-reticuline.39 Intramolecular carbon-carbon phenol coupling of (if)-reticuline by the P450-dependent enzyme salutaridine synthase (STS) results in the formation of salutaridine.40 The cytosolic enzyme, salutaridine NADPH 7-oxidoreductase (SOR), found in Papaver bracteatum and P. somniferum, reduces salutaridine to (7S)-salutaridinol.41 Conversion of (7S)-salutaridinol into thebaine requires closure of an oxide bridge between C-4 and C-5 by acetyl coenzyme A salutaridinol-7-0-acetyltransferase (SAT). The enzyme was purified from opium poppy cultures and the corresponding gene recently isolated (Fig.7.2).42,43 In the last steps of morphine... 

Strychnos usambarensis (Loganiaceae) [root] S. Am. Indian poison curare component Derived synthetically from morphine, a morphinan isoquinoline alkaloid from Papaver somniferum (opium poppy) (Papaveraceae) [aerial]... 

The capsules and stems of Papaver somniferum contain opiate alkaloids essential in medicine. They are classified into two groups, phenanthrene types (morphine, codeine, thebaine) and benzylisoquinoline types [papaverine and noscapine(narcotine)]. These two types of alkaloids show sharply specific pharmacological properties. It is noteworthy that morphinane alkaloids are formed from (-)-(/ )-reticuline, whereas most other alkaloids derive from (-l-)-(5)-re-ticuline 11). 

Frick S, Kutchan TM, Fist AJ. Increasing morphinan alkaloid production by overexpressing codeinone reductase in transgenic Papaver somniferum. Plant Biotechnol. J. 2007 5 26-37. 73. 

Opium poppy Papaver somniferum L., Papaveraceae) is one of the most important medicinal plants and has been cultivated since early centuries. Opium, the dried cytoplasm of a specialized internal secretory system called the laticifer, is normally collected from the unripe capsule. It is the source for the commercial production of medicinally important alkaloids, morphine, codeine, thebaine, noscapine and papaverine [130, 131], Fig. (61). Morphine, which has strong addictive property, is still the most effective analgesic for the treatment of mortal cancer patients in modem medicine. Codeine is commonly used as an antitussive. However, field cultivation of this plant has been limited since 1953 by the United Nations Opium Conference Protocol to prevent narcotic crimes. Therefore, establishing tissue culture technique for the production of morphinan alkaloids seems to be desirable not only for medicinal purpose but also for decreasing abuse of opiates. 

Opium, the sun-dried latex of the unripe fruit of Papaver somniferum, cultivated from early times for this drug, contains at least 23 alkaloids. Of the major alkaloids three—morphine, codeine, and thebaine—contain the morphinan ring system. 

Morphinan Alkaloids.—Extensive research on the biosynthesis of morphine (51) and related alkaloids in Papaver somniferum has allowed a detailed description of the pathway from the amino-acid tyrosine through reticuline (44), thebaine (46), and codeine (50) to morphine (51) (Scheme The incorporation of (R)-... 

Formula and data, see morphinan alkaloids. M. is the most important morphine (opium) alkaloid. M. is poorly soluble in boiling water and chloroform, soluble in alcohol, aqueous calcium and magnesium hydroxides and phenol. M. is obtained by extraction from the poppy Papaver somniferum. M. can be detected by sever color reactions (e. g. violet color with Fe in alkaline solution), particularly sensitive procedures are gas chromatography, mass spectroscopy, and radio-immuno assays. 

Hiroshi S, Kozuo S, Takeshi T (1962) Analysis of opium alkaloids and allied compounds. XV. Colorimetric determination of dihydrocodeine by ceric ammonium nitrate and 2,4-dinitrophenylhydrazine. Yakugaku Zasshi 82 1684-1687 Hodges CC, Rapoport H (1982) Morphinan alkaloids in callus cultures of Papaver somniferum J Nat Prod 45 481-485... 

T. Yoshikawa and T. Furya, Morphinan alkaloid production by tissues differentiated from cultured cells of Papaver somniferum, Flanta Med., 51 (1985) 110-113. 

Alkaloids of the morphinane group. If the tetrahydroisoquinoline alkaloid norlaudanosoline is written in such a way that part of the molecule is rotated around the dotted line (Fig. 280), the relationship to the morphinane-type alkaloids becomes obviously. The actual precursor of these compounds, however, is (R)-reticuline. It is probably attacked by a phenol oxidase (C 2.3.1) yielding a biradical which is stabilized by the formation of the dienone (- -)-salutaridine. After reduction of (-j-)-salutaridine closure of a new 0-heterocyclic ring results in the formation of thebaine. The alkaloids codeine and morphine are synthesized from thebaine in Papaver somniferum,... 

Noscapine or narcotine (3) is a phthalideisoquinoline alkaloid from plants of the Papaveraceae family. It is an important alkaloid from the opium poppy (Papaver somniferum L.), occurring in variable quantities (level ranges from 2% to 10%) [38]. Unlike opioid morphinane drugs, noscapine lacks hypnoanalgesic, euphoric, and respiratory depressant properties. Its main therapeutic application is as oral antitussive drug, which is indicated to treat nonproductive coughs [39, 40]. 

Hodges CC, Rapport H (1982) Morphinan alkaloids in callus cultures of papaver somniferum. J Nat Prod 45 481-485... 

Morphine (5) and codeine (methylmorphine) (6), two major morphinan-type alkaloids with an isoqninoline skeleton, are extracted from opium, the dried milky sap released from the immature finits of poppies (Papaver somniferum). Morphine and codeine can interact with opioid receptors distribnted in brain tissnes and the periphery, and are most widely nsed as narcotic analgesics, with codeine also having an antitussive effect [4, 25, 32]. 

Coutts IGC, Hamblin MR, Tinley EJ (1979) The enzymatic oxidation of phenolic tetrahydroiso-quinoline-1-carboxylic acids. J Chem Soc Perkin Trans 1 2744-2750 Davis VE, Cashaw JL, McMurtrey KD, Ruchirawat S, Nimit Y (1982) Metabolism of tetrahydro-isoquinolines and related alkaloids. In Bloom F, Barchas J, Sandler M, Usdin E (eds) Beta-carbolines and tetrahydroisoquinolines. Liss, New York, p 99 Furuya T, Nakano M, Yoshikawa T (1978) Biotransformation of (RS)-reticuline and morphinan alkaloids by cell cultures of Papaver somniferum. Phytochemistry 17 891-893 Gates M (1953) Conversion of codeinone to codeine. J Am Chem Soc 75 4340-4341 Graves JMH, Smith WK (1967) Transformation of pregnenolone and progesterone by cultured plant cells. Nature (London) 214 124 8-1249... 

Analysis of extracts obtained with cell cultures derived hom Papaver bracteatum and Papaver somniferum revealed the occurrence of thebaine in the former, of thebaine, codeine, and to a lesser extent of morphine in the latter material (Tables 1,2). Considering the many attempts to demonstrate morphinan alkaloids in cell cultures which remained unsuccessful and unreported, detection of occurrence would have been described until quite recently as a rare phenomenon. The availability of a radioimmunoassay and other improved analytical systems would explain the surge of reports of accumulation since 1980. According to recent analyses, concentrations of morphinan alkaloids are as low or lower than in leaf tissue (0.14% DW), and much lower than in dried latex, opium (ca. 20% DW). 

Table 2. Morphinan alkaloid accumulation in Papaver somniferum cell cultures...

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