Codeine and Thebaine

The three alkaloids concerned, morphine, codeine and thebaine, all behave as tertiary bases. Morphine contains two hydroxyl groups of which one is phenolic and the other a secondary alcohol group. On methylation of the phenolic hydroxyl codeine results. On oxidation, codeine is transformed into codeinone by conversion of the secondary alcohol group into a carbonyl group, and when thebaine is boiled with A-sulphuric acid for a few minutes, it is hydrolysed into codeinone and methyl sulphate, and in other ways thebaine has been shown to contain two methoxyl groups. That the relationship between the three alkaloids is close may be illustrated by the following slightly extended formula —... 

It follows from the evidence thus obtained that morphine, an consequently codeine and thebaine, must be built up from the comple... 

A characteristic feature of the action of the opium alkaloids is their simultaneous depressing and exciting action on the central nervous system. In this respect there is no clear line of demarcation between the morphine group—morphine, codeine and thebaine—and the papaverine-narcotine group, and as the series is ascended in the order, morphine, papaverine, codeine, narcotine, thebaine, narcotic action diminishes and power of rellex stimulation increases until in thebaine a strychnine-like effect is exhibited. 

It was postulated [152, 153] that the aryl amine is oxidized by direct oxygen transfer from Compound I to the substrate. In contrast, for the oxidation of alkaloids, e.g. morphine, codeine and thebaine (Eq. 12), to the corresponding N-oxi-des by hydrogen peroxide in the presence of HRP or crude enzyme preparation from poppy seedlings, a radical mechanism was proposed [154]. 

The first group contains the natural products morphine, codeine and thebaine, which have been isolated from the natural product opium. In addition, the group contains various semi-synthetic derivatives of morphine, codeine and thebaine, which are prepared by chemical modifications of these natural products... 

In fact, small amounts of morphine, 6-acetylmorphine, codeine, and thebaine, all opiate compounds, have been found in mammalian brain877 878 and have presumably arisen by the same pathway observed in plants (Fig. 25-10). However, there is no cross reactivity between morphine and alcohol in addicted mice,879 and acetaldehyde is probably not the addictive agent. Acetaldehyde is very reactive and may be responsible for much of the damage caused by ethanol.880 At a blood ethanol concentration of 20 mm a person is legally intoxicated, and large amounts of acetaldehyde may be formed and react with many amines, nucleotides, proteins, etc. Ethanol blocks glutamatergic NMDA receptors and... 

The opium alkaloids morphine, codeine, and thebaine have a phenanthrene nucleus (Figure 11.10 and Figure 11.11). 

The opium alkaloids, which are obtained from Papaver somniferum, contain two groups of compounds compounds with phenanthrene derivatives, consisting of morphine, codeine, and thebaine and compounds with isoquinoline derivatives, consisting of papaverine and noscapine. 

The alkaloids derived from opium are collectively known as opiates. Morphine, codeine, and thebaine are well-known opium derivatives. Paregoric is an opium tincture (opium in an alcohol mixture). 

The isolation of the cDNAs encoding the enzymes involved in diverse isoquinoline alkaloid formation in plants and microorganisms allowed the first metabolic engineering routes to be developed and paved the way for new ways of future production of isoquinoline alkaloids. For instance, transgenic opium poppy plants were created in which codeinone reductase was suppressed by RNAi, resulting in the substitution of morphine synthesis with the non-narcotic precursor reticuline [110]. In a similar approach, RNAi suppression or overexpression of salutaridinol 1-0-acetyltransferase in opium poppy led to accumulation of salutaridine or increase of morphine, codeine and thebaine content [111], suppression of the BBE led to accumulation of berberine in California poppy cells [112],... 

Carroll et al. confirmed the assignments made by Terui et al. for codeine and thebaine and investigated a large number of related compounds. They... 

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... 

THE REACTION OF 0-CODEINE AND THEBAINE DERIVATIVES WITH GRIGNARD REAGENTS... 

The Stork group reported the synthesis of racemic codeine and thebaine utilizing the intramolecular Diels-Alder reaction as the key transformation in 2009 [45]. The key features of their synthesis are (1) a direct construction of a phenanthrofuran skeleton (A-B-C-E tetracyclic system) by the intramolecular Diels-Alder reaction of a diene tethered to the benzofuran ring and (2) a formation of the D-ring by the intramolecular SN2 reaction of an amino-mesylate. 

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. 

The rate of change of morphine, codeine, and thebaine content with time in Papaver somniferum73 and the localization of these alkaloids in different segments of plant tissue72 have been studied. Examination of Korean opium from various... 

In addition, the ability of tissue cultures of Papaver somniferum to produce morphine, codeine, and thebaine has been further demonstrated.Of these alkaloids, norsalutaridine, 0-methylpallidine, pallidinine (80 R = H), 0-raethylpallidinine (80 R = Me), 8,14-... 

Robinson (12) wrote a review on the metabolism and function of alkaloids in plants in which references to morphine, codeine, and thebaine were given. Preininger (13) published a comprehensive review including 691 references on the pharmacology and toxicology of the Papaveraceae alkaloids. 

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). 

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