Benzylisoquinoline alkaloids papaverine

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. 

The capsules and stems of Papaver somniferum contain opiate alkaloids essential in medicine. They are classified into two groups, phenanthrene types (morphine, codeine, thebaine) and benzylisoquinoline types [papaverine and noscapine(narcotine)]. These two types of alkaloids show sharply specific pharmacological properties. It is noteworthy that morphinane alkaloids are formed from (-)-(/ )-reticuline, whereas most other alkaloids derive from (-l-)-(5)-re-ticuline 11). 

Opium contains over 50 alkaloids that fall into one of two chemical classes the phenanthrene class, including morphine and related derivatives and the benzylisoquinoline alkaloids, such as papaverine (58,Fig. 7.14 see Ref 291 for a complete listing of alkaloids present in opium). In addition to morphine, which on average accounts for 10-20%of opium, other re-... 

Papaverine and other benzylisoquinoline alkaloids have been isolated from Russian Kirghiz opium.70 Examination of opium samples from various localities in Korea has revealed that papaverine content does not vary from area to area.71 Four species of Papaveraceae have been examined for relative amounts of papaverine and other alkaloids in different segments of plant tissue.72 A study of the variation with time of papaverine content in the germinating seedling of Papaver somniferum has been reported.73... 

Compared to its companion alkaloids, papaverine has attained a dominant place in the benzylisoquinoline group, partly because more of it occurs in opium and its routine isolation is not too difficult, but chiefly because of its use in medicine. It is one of the few alkaloids manufactured synthetically, and its reactions have been explored with uncommon thoroughness. Because of the close connections between papaverine and the other members of this groups, the way for many of the reactions and syntheses of the minor alkaloids will be paved on the pages devoted to papaverine. 

Desgagne-Penix, I. and P. J. Facchini, Systematic silencing of benzylisoquinoline alkaloid biosynthetic genes reveals the major route to papaverine in opium poppy. Plant J., 2012. 72(2) p. 331-44. 

Benzylisoquinoline is the structural backbone of many alkaloids that possess potent therapeutic properties. Benzylisoquinoline alkaloids (BIAs) include the narcotic analgesics codeine and morphine, the antimicrobials sanguinarine and berberine, the anti-tussive and anticancer agent noscapine, and the muscle relaxants papaverine and tubocurarine. 

Papaver somnifemm (Papaveraceae) is a very important plant in the world, and is famous as the source material for Ahen (Opium), which is discussed subsequently (Section 1.10). From opium, papaverine and related alkaloids belonging to the benzylisoquinoline alkaloids were isolated, in additon to morphine and codeine, which belong to the morphine alkaloid series. Papaverine possesses smooth muscle relaxant activity and is used clinically. 

The predominant constituents of raw opium are alkaloids, fatty acids, sterols, alcohols, resins, sugars, and plant fragments. At least 30 alkaloids have been identified and have been classified into two categories, phenanthrenes and benzylisoquinolines. The phenan-threne alkaloids include morphine, codeine, and the-baine, and the benzylisoquinoline alkaloids consist of papaverine and noscapine. If not removed during preparation, many of these compounds will be present in heroin as minor contaminants. 

One of the simplest benzylisoquinolines is papaverine 6,124) which is formed from norlaudanosoline 6,123) [81-83]. The most complex are the bisbenzylisoquinolines, e.g. epistephanine (5.725), and so far it is established that coclaurine 6.126) is a key precursor for several of these alkaloids [84—86]. Coclaurine itself has a genesis similar to that outlined in Scheme 6.24 [87]. 

Recent developments in the biogenesis of the benzylisoquinoline alkaloids were briefly referred to in the introduction to this chapter furthermore, when dealing with each particular base, its role as biogenetic precursor of other alkaloids was mentioned. Although the advances have been considerable, little is known of the detailed metabolic pathways which lead to the biosynthesis of these alkaloids. Practically all the results obtained derive from the administration of labeled precursors. Enzymatic w ork is just beginning. We shall consider here only the biogenesis of papaverine (CIII) and reticuline (LI) which have been more thoroughly studied. 

That tyrosine plays a role in the biogenesis of several types of benzylisoquinoline alkaloids results from its incorporation to the hydrophen-anthrene bases (thebaine, codeine, morphine) and to the benzylisoquino-lines papaverine, narcotine, and narcotoline w hen the generally labeled amino acid was fed to P. somniferum 219). 

The tetrahydroisoquinoline skeleton occurs in numerous plant alkaloids. The simplest bearers of this structural unit are exemplified by anhalonidine (12) (Sect. 2). Slightly more elaborate are the benzylisoquinoline alkaloids exemplified at their simplest by reticuline (25) and papaverine (27) (Sect. 3). 

Opium is the dried, powdered sap of the unripe seed pod of Papaver somniferum, a poppy plant indigenous to Asia minor. Theophrastus described its medical properties in the third century BC, but the Sumerians, ca BC 4000, probably perceived its utility. Arab physicians knew of the dmg, and Arab traders carried it to the Orient where it was used as a treatment for dysentery. Paracelsus is credited with repopularizing the dmg in western Europe in the early sixteenth century by formulating opium into "laudanum", which is still in use. More than 20 different alkaloids (qv) of two different classes comprise 25% of the weight of dry opium. The benzylisoquinolines, characterized by papaverine [58-74-2] (1.0%), a smooth muscle relaxant, and noscapine [128-62-1] (6.0%), an antitussive agent, do not have any analgesic effects. The phenanthrenes, the second group, are the more common and include 10% morphine (1, = R = H), 0.5% codeine [76-57-3], C gH2 N03, (1, R = H, R = CH3), and 0.2 thebaine [115-37-7], C 2H2 N03, (2). 

These alkaloids have a phenyl or phenylpropyl nucleus. The group includes simple phenyl amine (tyramine, hordenine), catecholamine (dopamine, noradrenaline, adrenaline), simple tetrahydroisoquinoline (mescaline, anhalamine, anhalonine, anhalonidine), benzylisoquinoline (e.g., papaverine), phthalideiso-quinoline (e.g., noscapine), phenethylisoquinoline (autumnaline, floramultine and kreysigine), tetrahydroisoquinoline (emehne and cephaeline) and terpenoid tetrahydroisoquinoline (secologanin and ipecoside) alkaloids. 

Bischler-Napieralski and Pictet Spengler reactions continue to serve well for benzylisoquinoline syntheses.76,77 In the latter reaction, use of a-formylphenyl-acetic esters for the non-nitrogen-containing component appears to be advantageous.77 An interesting sequence of reactions (43)—>—>(44) (Scheme 4) has apparently been applied to the synthesis of papaverine [44 R = 3,4-(MeO)2-C6H3CH2 ] and related alkaloids.78 An attempt to convert ( )-reticuline (37 R = H) into a morphinandienone-type alkaloid by enzymic oxidation with... 

Of the six species classified by Fedde (70) in this section, only P. mac-rostomum Boiss. et Huet. has been studied (Table VII). The other species are morphologically closely related (46). Plants cultivated in central Europe (CSSR, GDR), were found to contain rhoeadine, papaverrubine, and protopine alkaloids in the same way as the species of the sections Orthorhoeades and Argemonorhoeades (40,47). Plants collected in the vicinity of Lake Sevan (Armenia) yielded macrostomine (40) as the major alkaloid together with dehydronor-macrostomine (43) and sevanine (37) (benzylisoquinolines of the papaverine type) but no rhoeadines or papaverrubines (48). These differences in the alkaloid content may be explained by the observation that P. macrostomum from Armenia... 

The biosynthesis starts from the amino acid tyrosine which is first hy-droxylated to DOPA (Fig. 129). Two units of DOPA provide the skeleton of the benzyl-isoquinoline. Norlaudanosoline is a key substance which has also been shown to be present, among others, in the genus Papaver. The rest of the benzylisoquinolines can be derived from it. Only two kinds of derivatives will be mentioned here, papaverine and morphine alkaloids. 

The pharmacological effects of this complex mixture of alkaloids in opium may, in some respects, be more beneficial than the effects of an individual alkaloid. The effect of opium in the treatment of diarrhoea is better than that of either morphine or codeine given individually. It is possible to calm the gastrointestinal tract with a dose which contains only half of the dose which would be necessary for morphine alone. The combination of the increase in stretch reflex caused by morphine and the inhibition of increased peristaltic action by papaverine leads to a better therapeutic effect. The increase in muscle tone due to morphine is reduced by papaverine, and other benzylisoquinolines also participate in this tranquillisation of the g.i. tract. In the normal 50 mg dosage of opium used for the treatment of diarrhoea there is about 5 mg of morphine, 0.5 mg of papaverine and 3 mg of nos-capine which contrasts markedly with a dose of 100—200 mg of papaverine if this were given alone. The analgaesic activity of opium is due mainly to the morphine present, as the levels of codeine, neopine and papaverine are relatively small. The respiratory depression effect of opium is also due to the morphine content and the antagonistic effects of noscapine and narcotoline are not so pronounced. Thus the main use of opium in medicine is for the treatment of diarrhoea. 

---