Morphinan alkaloids morphine

S)-Reticuline is also the precursor for the biosynthesis of benzophenanthri-dine (e.g. sanguinarine, marcarpine), protoberberine, berberine, palmatine) and morphinan alkaloids (morphine, codeine) (see next few paragraphs). 

Vitamin B12 (catalysis) ascorbic acid morphinan alkaloids (morphine, sinomenine, and codeine) pyridoxine sodium nitroprusside sulbactam sodium (enhanced CL) clavulanic acid (enhanced CL) captopril (enhanced CL)... 

Morphinane alkaloids—morphine, codeine, thebaine (phenanthrene derivatives)... 

A total of more than 20 total syntheses have been described which aim to generate the most important members of the morphinan-type alkaloids, morphine and codeine. These long-standing efforts in alkaloid synthesis have been primarily due to the exceptional pharmacological importance of both compounds, as the most efficacious therapies for pain and cough, respectively. 

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... 

Many opium-derived and other IQs are psychoactive, the best known being the analgesic, addictive, narcotic, opium-derived morphinan alkaloids codeine and morphine (heroin being the semi-synthetic diacetate of morphine). The tertiary or quaternary amine structural component is important for the activity of some Erytkrina alkaloids and bisbenzyliso-quinolines (notably the major curare component (+)-tubocurarine) as antagonists of the nACh-R involved in neuronal excitation of skeletal muscle. The planar disposition of some polycyclic benzophenanthridines enables intercalation (parallel interleaving) between the base pairs of DNA. A variety of naturally occurring and synthetic IQ compounds are protein kinase inhibitors. 

Morphine and related morphinan alkaloids (A) akuammine, mitragynine (A), ibogaine and related indole alkaloids... 

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). 

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. 

The alkaloid content of regenerated shoots was analyzed by ELISA and HPLC (Table 21). The regenerated shoots apparently could accumulate much more morphinan alkaloids than their original calli (approximately 1000-fold higher level of morphine equivalents for the non-transformants, 100-fold higher level of morphine equivalents for the transformants). The transformed shoots contained almost the same level of morphinan alkaloids as the non-transformed shoots when being analyzed by ELISA, but no morphine could be detected by HPLC. 

In the plant family Papaveraceae, morphinane alkaloids were found only in some sections and species of the genus Papat er. The occurrence of thebaine was observed in the sections Orthorl oeades, Mecones, Pilosa, and Macrantha whereas morphine and codeine were found only in... 

A commercially profitable biomimetic synthesis of morphinane alkaloids will require the conversion of reticuline into salutaridine in sufficient yield (Scheme 14) (see Section III,D) and the conversion of salutaridine into thebaine, codeine, and morphine. 

Ikonomovski studied the conditions of the methylation of morphine into codeine by using phenyltrimethylammonium methoxide (521). New developments in photochemistry have also been applied to the morphinane alkaloids the effects of diffuse sunlight or daylight transform codeine in solution (methanol or ethanol) into methylcodeine and ethylmorphine, and thebaine in organic solvents into 3-O-methyl-6-0-ethylmorphine and its 7V-oxide, diethylmorphine, and its -oxide (522). Thebaine was found to yield codeinone (47a) and methylcodeine (45b). 

The qualitative and quantitative determinations of morphinane alkaloids or their derivatives in opium were studied by application of different methods (278, 533, 534), by differentia] spectrophotometry (535, 536), thin-layer chromatography (509, 537, 538), gas chromatography in conjunction with mass spectrometry (539, 540), and high-speed liquid chromatography (thebaine) (327, 534). A procedure for the quantitative determination of morphine in opium by isotopic dilution has been developed (541). 

Thornber compared the presence of 11 benzylisoquinoline alkaloids in the plants of the Papaveraceae, Menispermaceae, Berberidaceae, Magnol-iaceae, Ranunculaceae, Tutaceae, Monimiaceae, Annonaceae, Aristolo-chiaceae, Lauraceae, and Nymphaceae, and he concluded that the alkaloids cularine and morphine (including codeine and thebaine) are present only in the genera Corydalis and Dicentra (alkaloid cularine) and in the genus Papaver (morphinane alkaloids) the hasubanonine and bisben-zylisoquinoline alkaloids do not occur in Papaver plants (838). 

Attempts have also been made to cultivate such a type of P. somniferum which would contain a large quantity of morphine/codeine alkaloids in the straw (846, 847). This material can be adapted agrotechnically for an easier industrial isolation of morphinane alkaloids by the Kabay method. 

The quantity of thebaine in P. bracteatum depends on the period of ripening and on the part of the plant. The largest quantity was found in the roots (0.5-1.0%/weight of dry drug) and in the poppy heads (0.23-1.40%) (849). Bohm studied the content of morphinane alkaloids (thebaine, oripavine, and codeine/morphine) in hybrids obtained by hybridization between P. somniferum, P. bracteatum, P. orientale, and P. pseudoorientale and their dependence upon the genetic milieu (847). 

Fig. 4. Biosynthesis of the morphinan alkaloids thebaine (192), codeine (198), and morphine (204).

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)-... 

The conversion of reticuline (44) into morphinan alkaloids, which occurs with loss of tritium from C-1 in P. somniferum (see above)," has been observed also for the formation of thebaine (46) in P. bracteatum, a plant which produces this alkaloid but not codeine or morphine. Radioactive 1,2-dehydroreticuline (47) labelled both reticuline (44) and thebaine (46), whilst radioactive reticuline again labelled thebaine (46). ° Codeinone (48) and codeine (50) are biosynthetic intermediates between thebaine (46) and morphine (51) in P. somniferum, and it was shown that (48) was efficiently reduced to (50) in P. bracteatumf It is apparent that alkaloid biosynthesis in the two plants is similar, with the important difference that in P. bracteatum the enzymes which effect demethylation of (46) are missing, and so biosynthesis goes no further than thebaine (46). 

Callus tissue of P. somniferum has been reported not to produce morphinan alkaloids but benzophenanthridine, protopine, and aporphine bases. Recent experiments have shown that (5)-reticuline from (R,S)-reticuline (41) administered to tissue cultures was transformed into (5)-scoulerine (52) and (5)-cheilan-thifoline (53) [(R)-reticuline was recovered unchanged]. Morphine, codeine, and thebaine were not metabolized by the culture but (—)-codeinone (48) was converted stereospecifically and in high yield into (—)-codeine (50), both by the culture and by a crude enzyme preparation from it. 

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