Morphine alkaloids bound

Codeine, 14-hydroxycodeine, neopine, and O-methylflavinantine have been isolated from Papaver bracteatum,146 flavinantine and amurine from Meconopsis cambrica,113 isosinoacutine from Stephania elegans,174 and a new alkaloid, tridictyophylline, for which the structure (96) was determined by X-ray crystallography, from Triclisia dictyophylla.175 Bound morphine, codeine, and thebaine have been found in P. bracteatum and P. somniferum,176 and the effect of the period of maturation of the plants on the yield of these three alkaloids from P. somniferum has been studied.177,178 Codeine has been isolated from cell suspension cultures of P. somniferum under conditions where no morphine, norcodeine, or thebaine could be detected.179... 

Crude opium. Opium crudum, Pharm. Eur. has a morphine content of 12-16% whereas the pharmacopoeias require 10%. The alkaloids are bound to meconic acid, lactic acid, fumaric acid and sulphuric acid. Opium has a very characteristic smell and can be identified microscopically by the occurrence of characteristic fragments from the wall of the capsule. 

In P. somniferum, the alkaloids appear to be stored in the vacuolar sap of the vesicles rather than membrane bound in this respect, the vesicles behave as normal vacuoles (268, 298, 513). However, evidence indicates that the stem latex and vesicles are translocated into the capsule during its rapid expansion after petal fall. During that time, the morphine itself is being synthesized and metabolized in the vesicle (more rapidly in the stem vesicles... 

Two of the principal alkaloids of opium are morphine (4-21%) and a a-narcotine (noscapine) (4-8%) (63). These alkaloids occur partially bound to meconic acid, which is diagnostic for opium. Morphine (58) and its salts are classified as narcotic analgesics. Codeine (62) also occurs in opium, in the concentration range 0.7-2.5%. Most codeine (62) is prepared by methylation of morphine. 

The recent finding of N-oxides of thebaine, a relatively minor alkaloid, codeine and morphine (Figure 6-28) by Phillipson et al. (1976) in P. bracteatum and P. somniferum (Halle strain) permits the speculation that they might be involved in active metabolism. Phillipson et al, found low yields of the three alkaloid N-oxides and suggested that they do not accumulate but are either transformed into other metabolites or returned to the corresponding bases. P. somniferum seeds contain bound forms of alkaloids (Sec. 6.9.2) which on hydrolysis yields tertiary bases (Fairbairn and El-Masry, 1968) and their finding of N-oxides offers one of the best plausible explanations at this time. 

Since it has been unequivocally proven by Stermitz and Rapoport (1961) that the biosynthetic sequence thebaine -> codeine morphine is irreversible, and since the transport of morphine had been made, very probably, the subject of other pertinent papers, Fairbairn and Wassel (1964) suggested the presence of some sort of bound morphine. This conclusion was strengthened by the study with [ C]-labeled tyrosine (Fairbairn et al., 1964) as a precursor. Biosynthesis of alkaloids in the isolated latex provided evidence for the variation in content of all alkaloids and the disappearance of morphine. This indicated that morphine is transformed into some nonal-kaloidal compounds in the latex itself rather than elsewhere in the plant. 

Finally Fairbairn and El-Masry (1968) succeeded in proving the existence of bound alkaloids in poppy seeds. Poppy seeds normally contain only traces of alkaloids. The authors discovered alkaloidlike substances, codeine among them, after acid hydrolysis or pepsin digestion of ground seeds. These compounds were radioactive if the maturing capsule had been fed radioactive morphine. They also reported formation of these alkaloidlike compounds as a result of the action of a crude enzyme preparation from the plant upon morphine. 

At the subcellular level, the morphine biosynthetic pathway combines several cytochrome P-450 enzymes, bound to ER membranes (Chou and Kutchan, 1998) with soluble enzymes that reside in ER derived vesicles, e.g. norcoclaurine synthase, or in the cytosol, e.g. codeinone reductase (Zenk, 1994 Facchini and St-Pierre, 2005). The diverse localization of the biosynthetic enzymes requires several transport steps of the intermediates between cytosol, vesicles and vacuoles. Only one of them has been characterized by pioneering experiments (Deus-Neumann and Zenk, 1986) vacuolar vesicles prepared from Fumaria capreolata accumulate (S)-reticulin or (S)-scoulerin via highly specific transporters, that discriminate between (S)- and (R) stereoisomer and exclude other benzylisoquinolines (sanguinarine, protopine, morphine) and alkaloids of unrelated families (e.g. indoles or tropanes). Uptake is energized by the pH gradient across the tonoplast. Accumulated... 

Fairbairn JW, El-Masry S (1967) The alkaloids of Papaver somniferum L. V. Fate of the end-product alkaloid morphine. Phytochemistry 6 499-504 Fairbairn JW, El-Masry S (1968) The alkaloids of Papaver somniferum L. VI. Bound morphine and seed development. Phytochemistry 7 181-187 Fairbairn JW, Steele MJ (1980) Bound forms of alkaloids in Papaver somniferum andP. bracte-atum. Phytochemistry 19 2317-2321... 

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