(b) The anti-tussive activity of iV-aralkyl derivatives of (-f)-morphinans does not parallel the analgesic action of the corresponding (—)-isomers. The ( + )-isomers of the strongly analgesic (—)iV-[2-(2-furyl)-ethyl]- and N-[2-(2-thienyl)-ethyl]-3-hydroxymorphinans, which are 60 and 45 times more strongly analgesic than (—)-3-hydroxy-iV-methyl morphinan, proved to be 3 to 5 times less effective as cough inhibitors than Dextromethorphan. This was equally true for their methyl ethers.

(c) Substitution at position 2 and formation of an TV-oxide reduced the anti-tussive property.

(c) Clinical use

After Isbell and Fraser(242-324) had established that Dextromethorphan did not possess any addictive properties, Cass et a/.(325_327), Capello and Di Pasquale(328), encouraged by the favourable results of the animal tests submitted this compound to clinical trials. These showed that 10-15 mg Dextromethorphan had the same activity as 15 mg codeine and was better tolerated(329), there being no symptoms of narcotic oreuphoricaction(33 0> 33 no habituation or addiction(332_334).

Dextromethorphan neither reduced(331) nor promoted(322) expectoration.

In view of these properties Dextromethorphan is used in medicine as an addiction-free, codeine-like cough remedy. It is particularly recommended for use in paediatrics*33 ° in different forms of bronchitis and persistent cough(331,335,336) in the therapy of different forms of phthisis(332-333,337). It is also successfully applied in aerosols(337,338).

According to Grafe(339) Dextromethorphan is also valuable in pleuritic puncture, pneumothorax, thoracoscopy and bronchoscopy. Guidi and Gar-din(340) describe its use in geriatrics.

4. Anti-rheumatic action of morphinans

The alkaloid Sinomenine, isolated from the roots of Sinomenium acutum, a climbing plant from the forests of Southern Japan, is the only compound found in nature which belongs to the series enantiomorphic to morphine. According to the literature Sinomenine has a therapeutic action in rheumatism0 49) and is used in Japanese medicine(341). The pharmacological properties of this compound and clinical results in the treatment of rheumatism have been described by Shigeru Takaori(342) who also discusses a possible mode of action.

The scanty indications on the use of Sinomenine in rheumatism therapy led Jürgens and Bächtold(343) to test, in the egg-white(344) and the Seixter(345) "rheumatism tests", ( + )-3-hydroxy-iV-methyl-morphinan (Dextrorphan) which, in the morphinan series, corresponds sterically to the natural product Sinomenine. It was shown that Dextrorphan is strongly active in both tests; for example even of the lethal dose caused a definite reduction of phenol red excretion which is about twice that obtained with 10 mg/kg of cortisone given orally.

In the clinical trials which followed, however, Dextrorphan was found to be inactive in chronic arthritis. On the other hand certain favourable effects were found in degenerative arthroses, tendinoses, spondylitis and scleroderma0 5 5).

5. Metabolism of morphinans

(a) Analytical methods

The interest awakened in the different morphinans was not confined to their pharmacodynamic properties but extended to their metabolism, their distribution in the living organism and to their metabolites. In order to be able to answer the questions which arose, analytical methods had first to be worked out for characterizing the compounds of the morphinan type itself and for the small amounts of metabolites isolated from biological material.

Of further interest was the analytical differentiation between, on the one hand, racemic and laevo-rotatory morphinans (e.g. Racemorphan, Levor-phanol) whose application is subjected to the laws governing the use of narcotics and, on the other hand, the ife*iro-rotatory isomers (e.g. Dextromethorphan) which are free from this control.

To deal with these problems a whole series of analytical methods was worked out. Most of these methods were similar to those already in use for the morphine alkaloids and the morphine-like analgesics.

Of the many methods proposed a few purely physical, like the estimation of ultraviolet(346) and infrared'347* spectra and the X-ray methods'348-349) are worthy of special mention. Others depend upon precipitation and crystallization procedures'3 5 35 5) or consists in the colorimetric estimation of the basic compounds'356).

As the therapeutic doses of (—)-3-hydroxy-jV-methyl-morphinan tartrate (Levorphanol, Dromoran'R)), owing to its strong analgesic action, are very small (1-5-2 mg), the amounts of administered product or of metabolites to be expected in biological material are minute and demand very sensitive methods for their detection. Kaiser and Jori'357,358) were the first to recommend paper chromatography for this purpose and developed an appropriate working technique which was soon improved by Jatzkewitz'359,360), Curry and P0WELL'361),BR0ssi,HAFLiGERandScHNiDER'362),ViDic'363,364), Wagner'365) and Bonnichsen et alP66> by varying the developing solvent, the detecting reagents and by the use of specially pretreated papers. An interesting development in paper chromatographic analysis is described by Fischer and Otterbeck'367); with it they were able to separate a mixture of 19 morphine derivatives and synthetic analgcsics.

In addition to the appropriate paper chromatographic methods other ways were found for estimating very small quantities of morphinans. Will-ner'368), for example, specially recommended paper electrophoresis when the results from chromatography are doubtful. The method was particularly suited for the separation of basic compounds.

A further possibility of identification is by microscopic characterization of isolated crystalline compounds are described by Brandstatter-Kunert, Kofler and Kostenzer'369).

In order to distinguish between the three forms of 3-hydroxy-iV-methyl-morphinan: Racemorphan, Dextrorphan, Levorphanol, Clarke'370-370 developed an elegant microchemical method. This was also applicable to the identification of their methyl ethers: Racemethorphan, Levomethorphan and Dextromethorphan = Romilar(R). Using the technique of the hanging microdrop and with a special reagent for each group of morphinans, the dextro-and /aero-rotatory isomers were found to give amorphous precipitates while those formed from the racemates were crystalline. With the help of this method which can be used for quantities as small as 0-2 ,ug an analytical differentiation between the addictive forms of 3-hydroxy- and 3-methoxy-iV-methyl-morphinans and the dextro-rotatory isomers is possible.

(b) Results

With the help of these methods metabolic products, mainly of the morphinans prepared on a technical scale, were investigated analytically.

Brossi, Hafliger and Schnider(362) showed that the morphinans were excreted by the organism partly unchanged and partly with elimination of substituent groups, while leaving the morphinan skeleton intact. On administering (+)-3-methoxy-jV-methyl-morphinan (Dextromethorphan) to dogs, these authors found in the urine, besides a small amount of starting material, 11-15 per cent of its metabolic products. The following three different metabolites of dextromethorphan could be identified:

— 0-8-3-7 per cent (+)-3-methoxy-morphinan formed by iV-demethylation

— 1-8-4-2 per cent (+ )-3-hydroxy-7V-methyl-m orphinan formed by splitting off of the methoxy group, and finally

— 1-7-3-0 per cent ( + )-3-hydroxy-morphinan formed by simultaneous splitting off the ether and by iV-demethylation.

On the other hand it is remarkable that these authors could not identify similar decomposition products after administration of (—)-3-hydroxy-iV-methyl-morphinan (Levorphanol) and (— )-3-hydroxy-7V-allyl-morphinan (Levallorphan).

Woods, Mellet and Andersen(372) shortly afterwards showed by using N-C14-methy 1-labelled levorphanol, that this compound was also demethy-lated in the body, proof of this being the formation of C1402 as a result of biological breakdown; this agrees with the results of similar experiments using morphine(373,374). According to Adler et a/.(375_378) codeine is also broken down partly to an iV-demethylated and partly to an 0-demethylated compound (morphine) but is also excreted as free or bound codeine. Similar results were observed with pethidine: it was found by Plotnikoff et al (379-381) an(j Burns et alP&2) to be demethylated at the nitrogen atom.

The biological breakdown of the morphinans is not confined to the N-methyl compounds. Mannering and Schanker(383,384) who studied the metabolism of (—)-3-hydroxy-jV-allyl-morphinan (Levallorphan, Lorfan(R))

identified (—)-3-hydroxy-morphinan, indicating partial deallylation. In experiments with rats they obtained, in quantities greater than the iV-deallylated compound, a substance of unknown structure containing an additional oxygen atom. A comparison with the oxidation product of morphine(385) and with the oxidation and photo-oxidation products of (+ )-3-methoxy-7V-methyl morphinan(206), both of which have been oxidized in the 10-position, led to the conclusion that the new oxygen atom was attached at another than at 10 position(383). The same authors isolated from the urine of rabbits a further metabolite of unknown structure.

In order to clear up the kinetics of enzymatic O- and iV-demethylation of morphinans and morphine derivatives Takemori and Mannering(386) examined the liver microsomes of mice treated with these compounds and have drawn attention to certain connections between chemical constitution and the demethylation reaction.

The demethylation found in the living organism could also be reproduced in vitro. Axelrod(387,388) showed that the liver is the only organ whose microsomal fraction is capable of carrying out an iV-demethylation of narcotics. His results were shortly afterwards confirmed and extended by several research workers, among them Mannering et a/.(389'390) and Herken et al.<391).

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