salutaridine, found as a minor alkaloid constituent in the opium poppy Papaver somniferum (Papaver-aceae). Only the original benzyl aromatic ring can be restored to aromaticity, since the tetrahy-droisoquinoline fragment is coupled para to the phenol function, a position which is already substituted. The alkaloid thebaine is obtained by way of salutaridinol, formed from salutaridine by stereospecific reduction of the carbonyl group. Ring closure to form the ether linkage in the-baine would be the result of nucleophilic attack of the phenol group on to the dienol system and subsequent displacement of the hydroxyl. This cyclization step can be demonstrated chemically by treatment of salutaridinol with acid. In vivo, however, an additional reaction is used to improve the nature of the leaving group, and this is achieved by acetylation with acetyl-CoA. The cyclization then occurs readily, and without any enzyme participation. Subsequent reactions involve conversion of thebaine into morphine by way of codeine, a process which modifies the oxidation state of the diene ring, but most significantly removes two O -methyl groups. One is present as an enol ether, removal generating neopinone, which gives codeinone and then codeine by allylic isomerization and reduction respectively. The last step, demethylation of the phenol ether codeine to the phenol morphine, is the type of reaction only achievable in the laboratory by the use of powerful and reactive demethylating agents, e.g. HBr or BBr3. Because of the other functional groups present, chemical conversion of codeine into morphine is not usually a satisfactory process. However, the enzymemediated conversion in P. somniferum proceeds smoothly and efficiently. The enzymic demethy-lations of both the enol ether and the phenol ether probably involve initial hydroxylation followed by loss of the methyl groups as formaldehyde (Figure 6.50).
The involvement of these O-demethylation reactions is rather unusual; secondary metabolic pathways tend to increase the complexity of the product by adding methyls rather than removing them. In this pathway, it is convenient to view the methyl groups in reticuline as protecting groups, which reduce the possible coupling modes available during the oxidative coupling process, and these groups are then removed towards the end of the synthetic sequence. There is also some evidence that the later stages of the pathway in Figure 6.50 are modified in some strains of opium poppy. In such strains, thebaine is converted by way of oripavine and morphinone, this pathway removing the phenolic O-methyl before that of the enol ether, i.e. carrying out the same steps but in a different order. The enzymic transformation of thebaine into morphine, and the conversion of (R)-reticuline into salutaridinol have also been observed in mammalian tissues, giving strong evidence that the trace amounts of morphine and related alkaloids which can sometimes be found in mammals are actually of endogenous origin rather than dietary.
Opium is the air-dried milky exudate, or latex, obtained by incising the unripe capsules of the opium poppy Papaver somniferum (Papaveraceae). The plant is an annual herb with large solitary flowers, of white, pink, or dull red-purple colour. For opium production, the ripening capsules, which are just changing colour from blue-green to yellow, are carefully incised with a knife to open the latex tubes, but not to cut through to the interior of the capsule. These latex tubes open into one another, so it is not necessary to incise them all. Cuts are made transversely or longitudinally according to custom. The initially white milky latex quickly oozes out, but rapidly turns brown and coagulates. This material, the raw opium, is then removed early the following morning, being scraped off and moulded into balls or blocks. Typically, these are wrapped in poppy leaves and shade-dried. The blocks may be dusted with various plant materials to prevent cohering. Fresh opium is pale to dark brown and plastic, but it becomes hard and brittle when stored.
Opium has been known and used for 4000 years or more. In recent times, attempts have been made at governmental and international levels to control the cultivation of the opium poppy, but with only limited success. In endeavours to reduce drug problems involving opium-derived materials, especially heroin, where extremely large profits can be made from smuggling relatively small amounts of opium, much pharmaceutical production has been replaced by the processing of the bulkier 'poppy straw'. The entire plant tops are harvested and dried, then extracted for their alkaloid content in the pharmaceutical industry. Poppy straw now accounts for most of the medicinal opium alkaloid production, but there is still considerable trade in illicit opium. In addition to opium, the opium poppy yields seeds, which are used in baking and are also pressed to give poppy seed oil. The remaining seed cake is used as cattle feed, and it is held that these poppy seed products cover all the growing expenses, with opium providing the profit. Poppy seeds do not contain any significant amounts of alkaloids.
The main producer of medicinal opium is India, whilst poppy straw is cultivated in Turkey, Russia, and Australia. Opium destined for the black market originates from the Golden Triangle (Burma, Laos, and Thailand), the Golden Crescent (Iran, Pakistan, and Afghanistan), and Mexico.
Crude opium has been used since antiquity as an analgesic, sleep-inducer (narcotic), and for the treatment of coughs. It has been formulated in a number of simple preparations for general use, though these are now uncommon. Laudanum, or opium tincture, was once a standard analgesic and narcotic mixture. Paregoric, or camphorated opium tincture, was used in the treatment of severe diarrhoea and dysentery, but is still an ingredient in the cough and cold preparation Gee's linctus. In Dover's powder, powdered opium was combined with powdered ipecacuanha (see page 344) to give a popular sedative and diaphoretic (promotes perspiration) to take at the onset of colds and influenza. Opium has traditionally been smoked for pleasure, but habitual use develops a craving for the drug followed by addiction. An unpleasant abstinence syndrome is experienced if the drug is withdrawn.
In modern medicine, only the purified opium alkaloids and their derivatives are commonly employed. Indeed, the analgesic preparation 'papaveretum ' (see below), which once contained the hydrochlorides of total opium alkaloids, is now formulated from selected purified alkaloids, in the proportions likely to be found in opium. Although the ripe poppy capsule can contain up to 0.5% total alkaloids, opium represents a much concentrated form and up to 25% of its mass is composed of alkaloids. Of the many (>40) alkaloids identified, some six represent almost all of the total alkaloid content. Actual amounts vary widely, as shown by the following figures: morphine (Figure 6.50) (4-21%); codeine (Figure 6.50) (0.8-2.5%); thebaine (Figure 6.50) (0.5-2.0%); papaverine (Figure 6.45) (0.5-2.5%); noscapine (narcotine) (Figure 6.51) (4-8%); narceine (Figure 6.51; see also Figure 6.63, page 340) (0.1-2%). A typical commercial sample of opium would probably have a morphine content of about 12%. Powdered opium is standardized to contain 10% of anhydrous morphine, usually by dilution with an approved diluent, e.g. lactose or cocoa husk powder. The alkaloids are largely combined in salt form with meconic acid (Figure 6.51), opium containing some 3-5% of this material. Meconic acid is invariably found in opium, but, apart from its presence in other Papaver species, has not been detected elsewhere. It gives a deep red-coloured complex with ferric chloride, and this has thus been used as a rapid and reasonably specific test for opium. In the
(narcotine) morphine 6-0-glucuronide
(narcotine) morphine 6-0-glucuronide
past, the urine of suspected opium smokers could also be tested in this way. Of the main opium alkaloids, only morphine and narceine display acidic properties, as well as the basic properties due to the tertiary amine. Narceine has a carboxylic acid function, whilst morphine is acidic due to its phenolic hydroxyl. This acidity can be exploited for the preferential extraction of these alkaloids (principally morphine) from an organic solvent by partitioning with aqueous base.
Morphine (Figure 6.50) is a powerful analgesic and narcotic, and remains one of the most valuable analgesics for relief of severe pain. It also induces a state of euphoria and mental detachment, together with nausea, vomiting, constipation, tolerance, and addiction. Regular users experience withdrawal symptoms, including agitation, severe abdominal cramps, diarrhoea, nausea, and vomiting, which may last for 10-14 days unless a further dose of morphine is taken. This leads to physical dependence, which is difficult to overcome, so that the major current use of morphine is thus in the relief of terminal pain. Although orally active, it is usually injected to obtain rapid relief of acute pain. The side-effect of constipation is utilized in some anti-diarrhoea preparations, e.g. kaolin and morphine. Morphine is metabolized in the body to glucuronides, which are readily excreted. Whilst morphine 3-O-glucuronide is antagonistic to the analgesic effects of morphine, morphine 6-O-glucuronide (Figure 6.51) is actually a more effective and longer lasting analgesic than morphine, with fewer side-effects.
Codeine (Figure 6.50) is the 3-O-methyl ether of morphine, and is the most widely used of the opium alkaloids. Because of the relatively small amounts found in opium, most of the material prescribed is manufactured by semi-synthesis from morphine. Its action is dependent on partial demethylation in the liver to produce morphine, so it produces morphinelike analgesic effects, but little if any euphoria. As an analgesic, codeine has about one-tenth the potency of morphine. Codeine is almost always taken orally and is a component of many compound analgesic preparations. Codeine is a relatively safe non-addictive medium analgesic, but is still too constipating for long-term use. Codeine also has valuable antitussive action, helping to relieve and prevent coughing. It effectively depresses the cough centre, raising the threshold for sensory cough impulses.
Thebaine (Figure 6.50) differs structurally from morphine/codeine mainly by its possession of a conjugated diene ring system. It is almost devoid of analgesic activity, but may be used as a morphine antagonist. Its main value is as substrate for the semi-synthesis of other drugs (see below).
Papaverine (Figure 6.45) is a benzylisoquinoline alkaloid, and is structurally very different from the morphine, codeine, thebaine group of alkaloids (morphinans). It has little or no analgesic or hypnotic properties put possesses spasmolytic and vasodilator activity. It has been used in some expectorant preparations, and in the treatment of gastrointestinal spasms, but its efficacy was not substantiated. It is sometimes used as an effective treatment for male impotence, being administered by direct injection to achieve erection of the penis.
Noscapine (Figure 6.51) is a member of the phthalideisoquinoline alkaloids (see page 339) and provides a further structural variant in the opium alkaloids. Noscapine has good antitussive and cough suppressant activity comparable to that of codeine, but no analgesic or narcotic action. Its original name 'narcotine' was changed to reflect this lack of narcotic action. Despite many years of use as a cough suppressant, the finding that noscapine may have teratogenic properties (i.e. may deform a fetus) has resulted in noscapine preparations being deleted. In recent studies, antitumour activity has been noted from noscapine, which binds to tubulin as do podophyllotoxin and colchicine (see pages 136 and 343), thus arresting cells at mitosis. The chemotherapeutic potential of this orally effective agent merits further evaluation.
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