Codeine formation

In the preliminary experiment for MAFF clone 1 in liquid culture using a 100 ml flask, the ratio of UC to DT tended to increase with the increase of rotation rates. In the case of Cephaelis ipecacuanha (section 1.4.2), the frequency of adventitious shoot formation on intemodal segments was 83.7% when cultured in a RDF, whereas it is below 30% when cultured in an airlift type fermenter. The inhibition of shoot formation might be related with the hydrodynamic stress produced by aeration and/or rotation. Therefore, a RDF was chosen for P. somniferum cultures because the production of DT seemed to be associated with the codeine formation. Since moderate growth and alkaloid accumulation and proliferation of DT were observed in WP medium, DT was cultured using WP liquid medium. 

The three alkaloids all yield characteristic products on treatment with hydrochloric acid. In this way morphine yields ajjomorphine, apparently by loss of water codeine also yields ajjomorphine, accompanied by other products, but thebaine yields, with dilute hydrochloric acid, thebenine, and with strong hydrochloric acid, morphothebaine. These two are respectively secondary and tertiary bases, so that in the formation of thebenine a heterocyclic ring has been opened and a tertiary... 

For instance morphine (1) can be detected by the formation of various quinones via apomorphine as intermediate [4, 12, 13]. All morphines with an OH group in the 6-position and a double bond (codeine, ethylmorphine etc.) first undergo an acid-catalyzed rearrangement according to the following scheme [12] ... 

The Husemann and Erdmann identification reactions for morphine and codeine in the DAB 9 (German Pharmacopoeia) involve the formation of the red-colored ortho-quinone (8) via apomorphine (5) under the influence of nitric acid with the simultaneous nitration of the benzene ring [15]. 

The asymmetric synthesis of (+)-Codeine 432 devised by White and colleagues included a Beckmann rearrangement to introduce the nitrogen atom in the carbocyclic structure (equation 182). Even though two isomeric lactams 430 and 431 were obtained as a result of the rearrangement, the preferential migration of the bridgehead carbon atom produced 430 as the predominant isomer. The synthesis of the non-natural enantiomer of Codeine was completed after oxidation, olefin formation and reduction. 

The most important other opium alkaloid is codeine. In contrast to morphine, codeine has a high oral-parenteral potency ratio due to less first-pass metabolism. Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and codeine-6-glucuronide. Approximately 10% is demethylated to morphine. The analgesic effect of codeine is due to the formation of these metabolites as codeine itself has a very low affinity for opioid receptors. The half-life of codeine in plasma is 2 hours. 

In the case of some drugs the molecular ion may be abundant in the mass spectrum. Figure 9.15 shows the mass spectrum of codeine, where the molecular ion at m/z 299 is the base peak. The extended ring structure of the molecule means that apart from the abundant molecular ion, the fragmentation of codeine is not easy to interpret because of the structural rearrangements which occur. The only other ion in the mass spectrum of codeine closely related to the molecular ion is at m/z 229 and formation of this ion involves some rearrangement of the ring structure. 

Cortisol into 7- 3-hydroxycortisol. Epoxidation Benzene into benzene 1,2-epoxide. N-oxidation Drug containing amino groups can undergo N-oxidation i.e. imipramine into imipramine N-oxide. 0-dealkylation This reaction probably Involves formation of an unstable hydroxy methyl Intermediate I.e. codeine Into morphine. 

Morphine and codeine biosynthesis (Samuelsson, 1999 Herbert et al., 2000 Novak et al., 2000) Studies on the biosynthesis of morphine have been carried out mainly on cell cultures mainly of Coptis japonica and species of Thalictrum. Two enzymes (tyrosine decarboxylase and phenolase) catalyze the formation of dopamine from one molecule tyrosine. Dopamine is also the key intermediate in the biosynthesis of mescaline. 

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],... 

Lotsch J, Rohrbacher M, Schmidt H, Doehring A, Brockmoller J, Geisslinger G (2009) Can extremely low or high morphine formation from codeine be predicted prior to therapy initiation Pain 144 119-124... 

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