Morphine and related alkaloids

The idea that the opium alkaloid morphine is a modified benzyliso-quinoline provided the key to the structure 6.152) for the alkaloid twisting of the benzylisoquinoline skeleton into that shown for reticuline (6.127) in (6.148) illustrates this relationship and suggests a possible biogenesis. This was later proved correct in the course of a study which is one of the classics of alkaloid biosynthesis. In the first experiments ever to be carried out with complex plant-alkaloid precursors, [1- C]- and [S- Cj-norlaudanosoline [as (6.123) were fed to opium poppies [99, 100]. They were found to label morphine (6.152), codeine (6.153) and thebaine (6.151) specifically, thus establishing that these alkaloids are indeed benzylisoquinoline derivatives. The key intermediate [101] proved to be reticuline (6.148). Both (R) and (5)-isomers were utilized, the latter by way of (6.155) [101, 102] which allowed its conversion into (i )-reticuline (6.148), the correct intermediate, with the same configuration as the three opium alkaloids [as (6.151).  

Ortho-para oxidative coupling of the diphenol, reticuline (6.148), can be conceived of as giving the dienone (6.149) which could afibrd thebaine (6.151) as shown [101]. This hypothesis is strongly supported by the observation that this dienone, (6.149), called salutaridine, is a constituent of opium poppies, is formed from radioactive tyrosine (6.94) and norlaudanosoline (6.123), and is a highly efficient and specific precursor for the opium alkaloids. The transformation of salutaridine (6.149) into thebaine (6.151) requires a further ring-closure, which occurs chemically when the two epimeric alcohols (6.150) are treated with acid. In contrast to the purely chemical reaction, only one of the alcohols was efficiently converted into thebaine in vivo, indicating that the reaction is enzyme mediated (and therefore part of normal biosynthesis). 

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Morphine and related alkaloids Codeine, morphine, thebaine... 

Morphine and related alkaloids are specific to the genus Papaver (Berberidaceae), although the antipodal series of alkaloids is distributed in the Menisperma-ceae. Early in the biosynthesis of morphine, an inversion at C-1 of (5)-reticuline occurs, followed by ortho-para benzylic coupling to afford salutaridine. Stereospecific reduction and cyclization-elimination affords the 4,5-Ether bridge and thebaine. The dominant pathway from this point involves neopinone, codeinone, codeine, and morphine. Again, most of the enzymes in this sequence were isolated and characterized by Zenk s group (Fig. 30). 

Many alkaloids have pronounced biological properties, and many of the pharmaceutical agents used today are derived from naturally occurring amines. Morphine and related alkaloids from the opium poppy, for instance, are used for pain relief atropine from the flowering plant Atropa belladonna, commonly called the deadly nightshade, is used as an anti-spasmodic agent for the treatment of colitis and ephedrine from the Chinese p smt Ephedra sinica is used as a bronchodilator and decongestant. 

A number of various derivatization reactions have been used, as shown in Table 14.25. The derivatization has been carried out as off-column or on-column derivatization, mostly in order to give morphine and related alkaloids with phenolic or alcoholic hydroxyl groups better gas chromatographic properties. Especially for quantitative determination of morphine in opium or biological material such derivatization was necessary. Street et al. found, however, that the problem of adsorption of a phenolic alkaloid, such as morphine, because of "active sites" on the solid support could be solved by deactivation of the solid support by treatment of it (diatomaceous earth) with benzoyl chloride in pyridine before coating it with the stationary phase. 

Recent Advances in the Synthesis of Morphine and Related Alkaloids... 

The first chapter, Recent Advances in the Synthesis of Morphine and Related Alkaloids, by Noritaka Chida, presents the racemic synthesis of morphine and related alkaloids by four research groups, and the chiral synthesis of those alkaloids by four research groups. This work has greatly contributed to progress in Organic Chemistry and Medicinal Chemistry. 

C.d. and u.v.-visible spectra are reported for solutions of the antitumour triterpenoid tingenone in aqueous sodium deoxycholate,83 and c.d. curves have been recorded for morphine and related alkaloids in cholesteric liquid crystals.84... 

It is now well accepted that small amounts of morphine and related alkaloids are not only present in many foods but are also synthesized normally by animals. Therefore the metabolism of exogenous morphine and related molecules calls for no processes outside of what must be usual metabolism [65, 66]. Normal human plasma has been found to contain... 

The proceedings of a symposium entitled Alcoholism and the Central Nervous System contain a section which summarizes recent work on the possible role of morphine and related alkaloids in alcohol addiction. Further information regarding pharmacological and toxicological properties of morphine and its analogues is available. ... 

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