Natural Opium Alkaloids

Codeine acts less on the stomach and bowel than does morphine but, when given in large doses, also causes constipation. It is excreted unchanged in the urine. Tolerance for codeine is difficult to develop, but cases of addiction to it have been reported. They are usually secondary to the use of morphine that is, the patient, addicted to morphine and unable to secure this drug, resorts to codeine. 

Codeine, when incubated with the livers of several mammalian species, is converted to morphine and formaldehyde. The biotransformation products identified in the urine following the administration of codeine include morphine, norcodeine, and free and bound codeine. 

Dihydrocodeine is somewhat less analgesic, whereas dihydroisocodeine is approximately as analgesic as morphine in comparable doses. Dihydrocodeine is essentially free of such side effects as respiratory depression, nausea, and mood changes induced by codeine and dihydroisocodeine. 

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Chemical Class-. Natural opium alkaloid phenanthrene derivative... 

Brand Name(s) Astramorph PF, Avinza, DepoDur, Duramorph PF, Infumorph, Kadian, M-Eslon, MS Contin, MSIR, MS/S, Oramorph SR, Rapi-Ject, RMS, Roxanol, Roxanol-T Chemical Class Natural opium alkaloid phenanthrene derivative... 

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

Overman et al. exercised the CBS reduction strategy during synthesis of the natural opium alkaloid (—)-morphine (50)21 (Scheme 4.3q). Enantioselective reduction of 2-allylcyclohex-2-en-l-one (51) with catecholborane in the presence of the (R)-oxazaborolidinc catalyst (l )-28a provided the corresponding (S)-cyclohexenol 52 in greater than 96% ee. Condensation of this intermediate with phenyl isocyanate, regioselective catalytic dihydroxylation of the terminal double bond, and protection of the resulting diol afforded 53 in 68% overall yield from 51. The ally lie silane 54 for the upcoming iminium ion-ally lsilane cycliza-tion step was obtained in 81% yield by a stereoselective Sn2 displacement of allylic carbamate. 

Opioids are analgesics that work by binding to the opioid receptors found on neurons in various areas of the brain and spinal cord as well as intramural plexuses that regulate the motility of the gastrointestinal and urogenital tracts. Opiates are by definition limited to natural opium alkaloids and their semi-synthetic derivatives. Morphine,... 

Opioids. Morphine [57-27-2] C yH NO, (8) the most prevalent and analgesicaHy potent of the naturally occurring opium alkaloids (qv), has been used as an anesthetic premedication for over one hundred years (93). It has also been used as an iv analgesic for the last four decades, and, since 1969, in high doses as an anesthetic agent (117). 

Relief from pain has been an age-old aspiration of humankind. Natural substances— opium alkaloids from the latex of the poppy (Papaver somniferum, the sleep-bringing... 

The history of the opium alkaloids is too well known to warrant repetition here, but the analgesics based on morphine (l)are too important to be left out of an account of natural products as leads. Thus we shall summarize the clinically more important developments... 

The separation of the various components of naturally occurring mixtures of opium alkaloids. 

The natural fluorescence of the opium alkaloids has been used to obtain a selective and sensitive detection method. In this way codeine has been detected (the detector operating with an excitation wavelength of 213 nm and a cut-off filter for the emission... 

The term opium alkaloids has been used rather loosely to cover all narcotic analgesics, whether they be synthetic compounds, partially synthetic, or extracted from plant material. To be precise, we should really only use the term for those natural compounds which have been extracted from opium—the sticky exudate obtained from the poppy (Papaver somniferum). The term alkaloid refers to a natural product which contains a nitrogen atom and is therefore basic in character. There are, in fact, several thousand alkaloids which have been extracted and identified from various plant sources and examples of some of the better known alkaloids are shown in Fig. 12.1. These compounds provide a vast library of biologically active compounds which can be used as lead compounds into many possible fields of medicinal chemistry. However, we are only interested at present in the alkaloids derived from opium. 

The opium alkaloid thebaine, although therapeutically useless (causes seizures and has little analgetic action), is important as the chemical starting point for the commercial synthesis of methyldihydromorphinone (Metopon), hydrocodone and hydromorphone, oxy-morphone, and the very interesting oripavine compounds (see later). Since these drugs are modifications of a natural alkaloid, they may be referred to as semisynthetic opiates. 

Noscapine (Nectadon) is a naturally occurring opium alkaloid with a structure and function similar to papaverine. It is antitussive and has no analgesic or additive properties. 

Noscapine (Nectadon) is a naturally occurring opium alkaloid with a structure and function similar to papaverine. It is antitus-sive and has no analgesic or addictive properties. Diphenhydramine and chlorcychzine are antihistaminic agents that also have antitussive properties. Dimethoxanate and pipazethate (Theratuss) are phenothiazine derivatives without analgesic but with weak antitussive and local anesthetic properties. 

Figure 2. Some Naturally Occuring Opium Alkaloids...

Papaveretnm. Concentrated opium Omnopon Pantopon. A mixture of the hydrochlorides of the opium alkaloids in their approximate natural proportions. Contains approx 50% morphine, 3% oodeine, 20% noscapine, and S% papaverine. Exhibits biological action of morphine and other alkaloids present in opium. Clinical evaluation in intravenous analgesia I. A. Catling et aL, Brit. Med. J. 281, 478 (1980). 

The same treatment with hydrochloric acid when applied to (—)-laudan-osine gave again mixtures of phenolic bases from which a product identical with the opium alkaloid laudanidine [(—)-laudanine, LII] could be isolated. (- -)-Laudanosine furnished the optical isomer of the natural alkaloid under analogous conditions (29). 

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