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Opium

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Opium

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Elisabeth Simarmata
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Alkaloids 349 Box 6.7 Opium (Opium is the air-dried mitky exudate, or latex, obtained by incising the unripe capsules ofthe opium poppy Papaver somniferim (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, just changing colour from blue-green to yellow, are carefully incised with a knife o open the latex tubes, but not to cut through tothe interior ofthe capsule. These latex tubes open into one another, so itis not necessary to ince them all. Cus are made transversely or longitudinally according to custom. The initially white milky latex quickly oozes fut, but rapidly turns brown and coagulates. This material, the raw opium, is then removed early the following morning, being collected by scraping from the capsule. Further incising and collection may be carried out over a period of about a week. The ‘aw opium is moulded into balls or blocks, and typically these are wrapped in poppy leaves and shade-dried. The blocks may be dusted with various plant materials to prevent cobering. Fresh opium is pale to dark brown and plastic, but it becomes hard and britle when stored. ‘Opium has been known and used for 4000 years or more, In recent times, attempls 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-40) alkaloids identified, some six represent almost all ofthe total alkaloid content. Actual amounts vary widely, as shown by the following figures: morphine (421%; Figure 6.53); codeine (0.8-2.5%; Figure 6.53); thebaine (0.5-2.0%: Figure 6.53); papaverine (0.5-2.5% Figure 6.47); noscapine (narcotine; 4-8; Figure 6.54); narceine (01-29; Figure 6.4, and see also Figure 6.65, page 339). A typical commercial sample of opium would probably have a morphine content of about 125. Powdered opium is standardized to contain 10% of anhydrous morphine, usually by dilution with an approved diluent, ez lactose or covoa husk powder. The alkaloids are largely combined in salt form with meconie acid (poppy acid; Figure 6.54), ‘opium containing some 3-S% of this material. Meconic acid is invariably found in opium, but apart from its presence in other Papaver species it has not een detected elsewhere. It gives a deep red-coloured complex with ferric chloride, and dhs has thus bbeen used asa rapid and reasonably specific test for opium. Inthe past, the urine of suspected opium smokers could also be tested inthis way. OF the main opium alkaloids, only morphine and narceine display acidic properties as well asthe 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 6.53) 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 further dose of morphine is taken. This leads to physical dependence Vowrek i 2cog 350 Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition 0. < on ‘o MeO Ho,c~ ~o~ ~co. imecone acid ‘OMe arsine © bye noscapine (careatine) roephine 6-0-slveuonide Figure 6.54 \hieh is difficult to overcome, so thatthe major current use of morphine is thus in the relief of terminal pain, Although orally active, to obtain rapid reli of acute pain i is usually injcted. 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 10 the analgesic effects of morphine, morphine 6-0-glucuronide (Figure 6.54) is actually a more effective and longer lasting analgesic than morphine, with fewer side-effects, such as nausea and vomiting. This ‘agent isin clinial trials for the treatment of cancer-related pain, Since it is significantly hydrolysed in the gut, itis much less effective taken orally than when administered by injection ‘Codeine (Figure 6.53) isthe 3-O-methyl ether of mogphine and isthe most widely used of the opium alkaloids, Because of the relatively small amounts found in opium, almost all of the material prescribed is manufactured by semi-synthesis from morphine. Its action is dependent on partial demethylation in the liver to produce morphine, soit produces morphine-like analgesic effects, but litle 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, It isa relatively safe non-addictive medium analgesic, but is still 100 constipating for long-term use. Codeine also has valuable antitussive action, helping to relieve and prevent coughing. Iteffectively depresses the cough centre, raising the threshold for sensory cough impulses ‘Thebaine (Figure 6.53) differs structurally from morphine/eodeine 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-symthesis of other drugs (see below. Papaverine (Figure 6.47) is a benzylisoquinoline alkaloid, and is structurally very different from the morphine, codeine, thcbaine group of alkaloids (morphinans). It has litle or no analgesic or hypnotic properties, but it relaxes smooth muscle in blood vessels. Is sometimes used as an effective treatment for male impotence, being administered by direct injection o achieve erection of the penis. The advent of orally active agents such as sildenafil (Viagra®) has presumably diminished this application. Noscapine (Figure 6.54) is a member of the phthalideisoquinoline alkaloids and provides a further structural variant in the ‘opium alkaloids. Noseapine has good antitusive and cough suppressant activity comparable to that of codeine, but no analgesic ‘oF narcotic ation. Its original name ‘narcotine’ was changed to reflect ths lack of narcotic aetion. Despite many years of use as & cough suppressant, the finding that noscapine may have teratogenic properties (ie. 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 ppodophyllotoxin and colchicine (See pages 155 and 361), thus arresting cells at mitosis. The chemotherapeutic potential ofthis orally effective agent merits further evaluation, Papaveretum is a mixture of purified opium alkaloids, as their hydrochlorides, and is now formulated to contain only morphine (85.5%), codeine (7.8%) and papaverine (6.7%). It is used for puin relief during operations. It may be combined with the antisecretory tropane alkaloid hyoscine (see page 318). ‘A vast range of semi-synthetc or totally synthetic morphine-like derivatives have been produced. These are collectively refered to as “opioids”. Many have similar narcotic and pain-relieving properties as morphine, but are less habit forming. Others possess the cough-relieving activity of codeine, but without the analgesic effect. More than 90% of the morphine extracted from opium (or poppy straw) is curently processed to give other derivatives (Figure 6.55). Most of the codeine is obtained by semi-synthesis from morphine, mono-O-methylation occurring atthe acidic phenolic hydroxyl. Similarly, pholeodine (Figure 6.55), an effective and reliable antitussive, can be obtained by alkylation with N-(chloroethyl)morpholine. Dihydrocodeine (Figure 6.55) is a reduced form of codeine with similar analgesic properties, the double bond not being essential for activity. In hydromorphone (Figure 6.55), the double bond of morphine has been reduced, and in addition the 6-hydroxyl has been oxidized to a ketone. This increases the analgesic effects but also the side-effects; the drug is used for severe pain associated with cancer. Diamorphine (or Alkaloids Box 6.7 (continued) HO. tute ui ° Isat Go visenaya | Po*PObINE ee Gp eriaen es wm 5 Aco Me:S0, price Me NMe a iss Wha (Giamorphin) ee Ha, catalys oJ °. ow Ho. é A ho au Me NMe Ainydroodeine polodine spomephine Figure 6.5, heroin; Figure 655), is merely the diacetate of morphine iti a highly addictive analgesic and hypnotic. The inereased lipophilic character of heroin over morphine results in improved solubility, with beter transport and absorption, though the active agent is probably the G-aceiate, the 3-acetate group being hydrolysed by esterases in the brain. Heroin was synthesized orig as a cough suppressant; and though most effective inthis role, it has unpleasant adlctve properties, with users developing & psychological craving for the drug. It is widely used for terminal care, eg. cancer sufferers, both as an analgesic and cough suppressant. The euphoria induced by injection of heroin has resulted in much abuse of the drug and creation of a worldwide ‘major drug problen ‘The N-methyl group of morphine can be removed by treatment with cyanogen bromide, then hydrolysis. A. variety of ‘N-alkyl derivatives, eg. N-allyl-normorphine (nalorphine; Figure 6.55) may be produced by use of appropriate alkyl bromides. Nalomhine has some analgesic activity, hut it was also found to counter the effects of momphine and is thus a mixed agonist-antagonist. It has been used as a narcotic antagonist, but i principally regarded as the forerunner of pure opiate antagonists such as naloxone (See below), Treatment of morphine with hot acd induces a rearrangement process resulting in a highly modified Structural skeleton, a representative of the aporphine group of alkaloids (see page 355). The product apomorphine (Figure 6.55) hhas no analgesic properties, but momphine’s side-effects of nausea and vomiting are highly emphasized. Apomorphine isa powerful emetic and can be injected for emergency treatment of poisoning. This is now regarded as dangerous, but apomorphine is curently valuable to control the symptoms of Parkinson's disease, being a stimulator of D and Ds dopamine receptors. Apomorphine’s structure contains a dihydroxyphenylethylamine (dopamine) fragment conferring potent dopamine agonist properties to this agent (ee page 336) 352. Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition Me“ orl meen 7-H * chiral centre oO ‘on ‘OH phenylpiperidine tyrosine-like system in morphine residue in morphine Figure 6.56 It has been found that a common structural feature required for centrally acting analgesic activity in the opioids is the combination of aromatic ring and a piperidine ring which maintain the stereochemistry atthe chiral centre, as shown in Figure 6.56. The three-limensional disposition of the nitrogen function to the aromatic ring allows morphine and other analgesics to bind to pain-reducing receptors in the brain. Three distinct classes of opioid receptors, 8, and x, have been distinguished; ‘morphine acts primarily at y-receptors. Morphine isnot the natural ligand for opioid receptors; the natural agonists are peptides termed opioid peptides (see page 434). These include enkephalins, endorphins, dynorphins, and endomorphins, All contain a terminal tyrosine residue in their structures, and it this feature that is mimicked by the morphine structure, allowing binding to the appropriate receptor (Figure 6.56). The opioid peptides themselves are rapidly degraded in the body and are currently unsuitable for drug use. ‘Some totally synthetic opioid drugs modelled on morphine are shown in Figure 6,57. Removal of the ether bridge and the functionalities inthe cyclohexene ring are exemplified in evomethorphan and dextromethorphan. Levomethorphan has analgesic properties, whilst both enantiomers possess the anttussve activity of codeine. In practice, the "unnatural" isomer dextromethorphan is the preferred drug material, being completely non-addictive and possessing no analgesic activity. Pentazocine isan example of 1 morphine-like structure where the ether bridge has been omitted and the eyclohexene ring has been replaced by simple methyl groups. Pentazocine has both agonist and antagonist properties, and although itis a good analgesic, it ean induce withdrawal sympioms. Even more drastic simplification of the morphine structure is found in pethidine (meperidine), one of the most widely used synthetic opiates. Only the aromatic ring and the piperidine systems are retained. Pethidine is less potent than ‘morphine, but produces promp, short-acting analgesia, and is also less constipatng than morphine, It can be addictive, Fentanyl has a 4-anilino~ rather than a 4-phenyl-piperidine structure, and is 0-100 times more active than morphine due to its high lipophilicity and excellent tansport properties: it can be administered transdermally via a patch. AMfentanil and remifentanil are further variants on the fentanyl structure; all three drugs are rapid-acting and used during operative procedures. The piperidine ring system is no longer present in methadone, though this diphenylpropylamine derivative can be drawn in such a way as 10 ‘mimic the piperidine ring conformation. Methadone is orally active, has similar activity to morphine, but is less cuphorigenic and has a longer duration of action. Although it is as potentially addictive as morphine, the withdrawal symptoms are different ‘and much less severe than with other drugs such as heroin, so that methadone is widely used for the treatment and rehabilitation of heroin addicts. However, it only replaces one addiction with another, albeit a less dangerous one. Dipipanone is structural variant on methadone, and is used for moderate to severe pain; i i usually administered in combination with an ani-emetic Diphenoxylate is used as an antdiarthoeal; t© minimize its habit-forming properties and potential abuse it is combined with 1 sub-therapeutic amount of the anticholinergic atropine (see page 318). Dextropropoxyphene contains an ester function but rmimies the piperidine ring ina rather similar manner. This agent has only low analgesic activity, about half that of codeine, and finds application in combination formulations with aspirin or paracetamol, Meptazinol is structurally unlike the other opiate ‘analgesies, in that it contains a seven-membered nitrogen heterocycle. It isan effective analgesic, and it produces relatively few side-effects with a low incidence of respiratory depression. Tramadol is a recent drug claimed to produce analgesia by two ‘mechanisms, an opioid mechanism and also by enhancement of serotoninergic and adrenergic pathways. It produces few typical opioid side-effects ‘Thebaine, for many years regarded as an unwanted by-product from opium. is now the raw material for semi-synthesis of several useful drugs. On treatment with hydrogen peroxide, the conjugated diene undergoes 1 4-addition, and hydrolysis results in formation of a 4-hydroxy cyclohexenone system (Figure 6.58). Reduction and demethylation lead respectively to oxycodone and oxymorphone, which are potent analgesics. The conjugated diene system in thebaine can also be exploited in a Diels-Alder reaction, building on yet another ring system (Figure 6.59), Some of these adducts have quite remarkable levels of analgesic activity, but are t00 powerful for human use. Some, e.. etorphine (Figure 6.59), are used in veterinary practice to sedate large Alkaloids Box 6.7 (continued) Ho. ° Ho: ‘morphine Ho. ‘dextromethorphan pentazocine (enantiomer = levonethorphan) QO Ay on wor EQ AR, pethidine fentanyl alfentanil (meperidine) moe W—\ NN COmMe FN NMes 7% os ‘meptazinol ‘Mey Figure 6.57 animals (elephants, rhinos) by means of tranquilizer darts. Etorphine is some 5000-10000 times more potent than morphine. ‘Buprenorphine (Figure 6.59 is an etorphine analogue with an N-cyclopropylmethyl substituent and rrt-buyl instead of n-propyl {nthe side-chain, This material has both opioid agonist and antagonist properties. Mixed agonist-antagonist properties offer scope for producing analgesia whilst negating the effects of other opioids to which a patient may be addicted. Buprenorphine has a Jong duration of action and only low dependence potential but it may precipitate withdrawal symptoms in patients dependent tm other opioids In| edison ts use aan acalgescy iis mow being uted as ar altermitve to mcthedone in| treatment of ‘opioid dependence. Nalbuphine (Figure 6.58), produced semi-sytheticaly from thebaine, also displays mixed agonist-antagonist properties and has similar agonist activity as morphine, but it produces less sideefTects and has less abuse potential. Naloxone (Figure 6.58) shows hardly any agonist activity, but itis a potent antagonist at all opioid receptors and is used to treat opiate poisoning, including that in children born to heroin addicts. Naltrexone (Figure 6.58) also has antagonist activity similar to naloxone. These agents are N-alkyl derivatives related to oxymorphoneloxycoxone. ‘Thebaine may also be transformed very efficiently into codeine in about 75% yield (Figure 6,58), The two-stage symhesis involves acid-catalysed hydrolysis of the enol ether function to give codeinone (this being the more favoured tautomer of the 354 Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition MeO. I4-addition MeO. Inydrolysis of. todiene Femikeral i, Ww —_ © —_ 'NMe Noe a Sn me v0 | ler Meo, Eee ‘NMe ‘NMe ~— o a eee ae ant, | edo rom 4 Yo less-hindered side ™ x \ HO. HO. o o NMe Ny Hi ho” NS 4 0’ oF HO" ‘ovleine naloxone naltrexone nalbuphine Meo. HO" Figure 6.8 firs-formed conjugated enol) followed by stereospecific borohydride reduetion of the carbonyl. This opens up possibilities for producing codeine (the most widely used ofthe opium alkaloids) without using morphine. At present, almost all of the codeine tused is synthesized by methylation of morphine, The advantage of using thebaine is that the raw material forthe pharmaceutical Industry could be shifted away from morphine and opium. This might then help in the battle to eliminate illicit morphine production and its subsequent conversion info heroin, Conversion of thebaine into morphine and heroin is much more dificult and low yielding. Thus, considerable effort has been put into selecting thebaine-tich varieties of Papaver somniferum and cultivating these for alkaloid production. A significant proportion of the poppy erop in Australia and France is now composed of thebaine-rich varieties. These strains produce thebaine and oripavine (Figurer 6.53) as main alkaloids, and appear to lack enzymes that carry cout the late demethylation steps in Figure 6.53. Most species of Papaver seem to lack the enzyme that reduces salutaridine 10 salutaridinol (Figure 6.53) and, thus, they do not synthesize mombine-like alkaloids. Oripavine (G-lemethylthchaine) may he used in the same way as thebaine in the synthesis of drugs. Metabolic engineering would seem to offer scope for modifying the alkaloid patterns in Papaver somniferun, In one study. the lte step catalysed by codeinone reductase has been blocked by gene silencing through RNA. interference: supplying a short strand of RNA to target that portion of mRNA responsible for a pantcular enzyme. Morphine and codeine production was markedly diminished, but other morphinan alkaloids, such as thebsine and oripavine, were aso suppressed, Instead, the major alkaloids accumulating were reticuline and some ofits methyl ethers The metabolic block appeared to be several steps further back in the pathway than predicted. Alkaloids 355 Box 6.7 (continued) ° eee me = 0. tae sereorelicly on Zt pa B from lesshindered side 8 OMe eo. ome MeN ome PrMel NaOH. o 6 ° demetyaion ie eee ome OMe on thebsine toring torphine buprenorphine Figure 6.59 Remarkably, there is now considerable evidence that various animals, including humans and other mammals, are also able to synthesize mogphine and retted alkaloids in small amounts. These compounds have been detected in various tssues, including brain, liver, spleen, adrenal glands, and skin, and endogenous morphine may thus play a role in pain relief, combining its effects with those provided by the enkephalin peptides. A minor constituent of Papaver somniferum is the apor- phine alkaloid isoboldine (Figure 6.60). Other species of poppy, €-g. Papaver orientale and Papaver pseu- doorientale, are known to synthesize aporphine alkaloids rather than morphinan structures as their principal con- stituents. Aporphines constitute one of the largest groups of isoquinoline alkaloids, with more than 500 representa- tives known, Apomorphine (Figure 6.55), the acid rear- rangement product from morphine, is a member of this ‘group, though is not a natural product, A cytochrome -450-dependent enzyme catalysing the ortho-ortho ox- dative coupling of (S)-reticuline to (S)-corytuberine (Figure 6.60) has been characterized from Coptis japonica (Ranunculaceae), a plant that also synthesizes berber- ine (see below). (S)-Isoboldine is readily appreciated to be the product of a similar oxidative coupling of (S)-reticuline, though coupling ortho to the phenol group in the tetrahydroisoquinoline portion and para to the phenol of the benzyl substituent (Figure 6.60). Some structures, e.g. isothebaine (Figure 6.60) from Papaver orientale, are not as easily rationalized, (S }-Orientaline is a precursor of isothebaine (Figure 6.61). This benzylte- trahydroisoquinoline, with a different methylation pattern to reticuline, is able to participate in oxidative coupling, but inspection of the structures indicates a phenol group appears to be lost in the transformation. The pathway (Figure 6.61) involves an unexpected rearrangement pro- cess, however, Thus, oxidative coupling ortho-para to the phenol groups gives a dienone orientalinone (com- pare the structure of salutaridine in Figure 6.53). After reduction of the carbonyl group, a rearrangement occurs, restoring aromaticity and expelling the hydroxyl (ori nally a phenol group) to produce isothebaine. This type of rearrangement, for which good chemical analogies are available, is a feature of many other alkaloid biosyn- thetic pathways and occurs because normal Keto-enol

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