Codeine alkaloids

Estimation of Other Alkaloids in Opium. Of the other alkaloids the most important is codeine, and processes for its estimation in opium have been described by Cespari, Andrews,and Annett and co-workers methods for its assay in admixture with other drugs in tablets and other products are also available. The estimation of papaverine has been described by Issekutz,i and of narcotine by Snesarov. As to methods for the separation and estimation of two or more of these subsidiary alkaloids, codeine and narcotine have been dealt with by van der Widen,narcotine and papaverine by Annett and Bose, ( and the bromination of codeine and narceine has been studied by Vaisberg et al. with a view to estimation by this means. 

This experiment33 illustrates how adjustment of pH may be used to control fluorescence and so make the determination more specific. The alkaloids codeine and morphine can be determined independently because whilst both fluoresce strongly at the same wavelength in dilute sulphuric acid solution, morphine gives a generally negligible fluorescence in dilute sodium hydroxide. The fluorescence intensities of the two compounds are assumed to be additive. 

Alkaloids (codeine, brucine), phenothiazines (promethazine), sulfonamides (sulfathiazole), vitamins (axerophthol, cholecalciferol)... 

Opium alkaloids [Codeine (12), Morphine (13)] Papaver somniferum L. (opium poppy) Antitussive Narcotic analgesic... 

An alkaloid is a complex organic chemical substance found in plants, which characteristically combines nitrogen with other elements, has a bitter taste, and typically has some toxic, stimulant, analgesic effects. There are many different alkaloids, 30 of which are found in the opium plant. While morphine is the most important alkaloid in opium—for its natural narcotic qualities as well as providing the chemical structure for heroin—another alkaloid, codeine, is also sought after for its medicinal attributes. Other alkaloids include papaverine, narcotine, nicotine, atropine, cocaine, and mescaline. While the concentration of morphine in opium varies depending on where and how the plant is cultivated, it typically ranges from 3 percent to 20 percent. 

Natural opium alkaloids codeine phosphate hydromorphone hydrochloride morphine hydrochloride morphine sulfate oxycodone hydrochloride oxymorphone hydrochloride... 

Opium alkaloids and derived phenanthrene alkaloids codeine, morphine, (Avinza, Kadian, MSContin, Roxanol), hydromorphone (Dilaudid), oxymorphone (Numorphan), oxycodone (dihydroxycodeinone, a component of Oxycotin, Oxydose, Oxyfast, Percodan, Percocet, Roxicodone, Tylox)... 

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

The opium alkaloids codeine and morphine served as models for the synthesis of naloxone, an important analog used to treat and diagnose opiate addicts, and also led to the discovery of endogenous opioids (enkephalins and endorphins) (see Chapter 47). Similarly, A9-tetrahydro-cannabinol (THC), the component of Cannabis sativa responsible for the central nervous system (CNS) effect, has also been found to reduce nausea associated with cancer chemotherapy (see Chapter 18). 

This intermediate gives rise to the important alkaloids codeine and morphine, which differ only by a methyl group. Nature can remove methyl groups as well as add them. 

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. 

The SARs of compounds structurally related to morphine are outlined in Table 24.2. A number of the structural variations on morphine have yielded compounds that are available as drugs in the United States. The most important of these agents, in terms of prescription volume, is the alkaloid codeine. Codeine, the 3-methoxy derivative of morphine, is a relatively weak p agonist, but it undergoes slow metabolic 0-demethylation to morphine, which accounts for much of its action. Codeine also is a potent antitussive agent and is used extensively for this purpose. 

Opioids are those substances that can activate localized opioid receptors in the pain-controlling system of the body. Their action can therefore be antagonized by naloxone. From a clinical point of view, morphine is the most important substance of this group. It is obtained from opium, which is the brownish latex obtained from cuts made in the unripe but fully grown fruits of Papaver somniferum, the opium poppy. Opium contains not only morphine but also over thirty other alkaloids (Fig. 8-13) including the isoquinoline alkaloids codeine, papaverine, noscapine, thebaine and others, which make up ca. 25% of the opium. The alkaloids in opium are sometimes present as salts of meconic acid. The opiates form a separate subgroup within the opioids whose member... 

EC is currently the most popular method for the determination of morphine in body fluids, since morphine contains a phenol group which is easily oxidized (Tagliaro et al. 1989). The detection limit of morphine typically varies from a few tens of picograms to several hundred. Other opiates contain a tertiary alicyclic amine, and can best be detected using a neutral or slightly alkaline eluent and about a 0.3-0.4 V higher potential than for morphine (Schwartz and David 1985). For the nonphenolic alkaloids, codeine has been detected by EC in body fluids at the nanogram level. However, EC has seldom been used for the determination of opium alkaloids in plant material. 

Figure 6.19 Biosynthesis of benzylisoquinoline alkaloids codeine and morphine.

Opitim contains 10-25% alkaloids, and the main constituent is morphine. Other than morphine, more than 25 alkaloids are known, and among them are other morphinan-type alkaloids (codeine and thebaine), benzyl-isoquinoline-type alkaloids (papaverine and noscapine), and protopine-type alkaloids (protopine). The biosynthetic precursor of all of these alkaloids is phenylalanine. 

Although a large variety of compounds can reduce tris(2,2 -bipyridyl)ruthenium(III), only certain species (e.g., aliphatic amines, amino acids, NADH, some alkaloids, aminoglycoside or tetracycline antibiotics, and the oxalate ion) will produce the characteristic orange luminescence with this reagent. Subtle differences in chemical structure can have a dramatic effect on chemiluminescence intensity. This is exemplified by the determination of the papaver alkaloid codeine (11) compared to structurally similar morphine (12). At pH 6.8, codeine can be determined down to a concentration of 10 mol 1 whereas morphine produces a chemiluminescent response equivalent to that of the blank. In many applications this degree of selectivity is most desirable. 

Codein phosphate and hydrochloride caused contact dermatitis in a worker in the production of opium alkaloids. Codeine bitartrate caused contact dermatitis in a worker in the production of concentrated poppy straw. Codeine was a sensitizer in a laboratory worker at an opiate-manufacturing pharmaceutical company, also sensitive to thebaine. 

Alkaloids of the morphinane group. If the tetrahydroisoquinoline alkaloid norlaudanosoline is written in such a way that part of the molecule is rotated around the dotted line (Fig. 280), the relationship to the morphinane-type alkaloids becomes obviously. The actual precursor of these compounds, however, is (R)-reticuline. It is probably attacked by a phenol oxidase (C 2.3.1) yielding a biradical which is stabilized by the formation of the dienone (- -)-salutaridine. After reduction of (-j-)-salutaridine closure of a new 0-heterocyclic ring results in the formation of thebaine. The alkaloids codeine and morphine are synthesized from thebaine in Papaver somniferum,... 

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. 

Morphinan alkaloids are the pharmaceutically most important class of isoquinoline alkaloids. Codeine and morphine are found only in Papaver somniferwn and closely related species. Both alkaloids are derived from (R)-reticuline, the absolute stereochemistry of which corresponds with the configuration of morphinan alkaloids. Re-ticuline is therefore an important branch point in isoquinoline bio nthesis. However, either enantiomer of reticulme, when fed separately, is incorporated into morphinan alkaloids essentially to the same extent. The question therefore arises by which mechanism (R)-reticuline is formed within the plant. 

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