Papaverine, isolation

The first scheme for the separation of the six chief alkaloids of opium, VIZ., morphine, codeine, thebaine, papaverine, narcotine and narceine, is probably that of Plugge. Much later Kljatschkina investigated for each of these six bases the properties by means of which isolation and estimation could probably be effected and, on the basis of the results, devised a plan for such analyses. More recently Anneler has published a detailed account of a scheme with the same objective. l Attention had already been given to complex, systematic analyses of this kind, in connection with examination of the mixtures of opium alkaloids, which have long been in use in medicine in these at first only morphine and other alkaloids were determined, but in the more recent schemes provision is made for the estimation of each alkaloid. ... 

Papaverine, C20H21O4N. This alkaloid, first obtained by Merck, occurs in the mixture precipitated by ammonia from the mother liquors of opium extract from which morphine and codeine have been separated in Gregory s process, and methods for its isolation from this mixture have been published by Hesse and others. The alkaloid may be purified by conversion into the acid oxalate, B. H2C2O4, m.p. 196° or 201-5-202°, which is nearly insoluble in alcohol. 

Papaverine was condensed with formaldehyde to methylenepapaverine (XXII), which on successive catalytic and electrolytic hydrogenation yielded two dZ-methyltetrahydropapaverines (XXIII), which on successive demethylation, condensation with formaldehyde and re-methylation yielded a mixture of bases, from which the two optically inactive corydalines (XXIV), jwesocorydaline, m.p. 163-4° (nac.), and dZ-corydaline, m.p. 132-3°, identical with the products obtained by the hydrogenation of dehydrocorydaline were isolated. For the conversion of corycavine to corydaline, see p. 304. 

Minor Corydalis Alkaloids. The following four alkaloids have been isolated by Manske from various Corydalis species but have not yet been assigned to chemical groups. Cularine has been compared pharmacologically with papaverine and hydrastine, and may prove to be related to one of these alkaloids. 

Pharmacological Action. As already pointed out, cularine shows some resemblance to papaverine and hydrastine in action (p. 196). The M.L.D. (mgm./kilo.) for mice by intravenous injection of ochotensine is 10-6 i 0-54 so that it seems to be the most toxic of the fifteen corydalis alkaloids examined by Anderson and Chen, who also state that it stimulates isolated guinea-pig or rabbit uterus, inhibits isolated rabbit-intestine and induces a fall in blood pressure on intravenous injection in etherised cats. 

Papaverine (107) is among the host of minor alkaloids that have been isolated from opium. The compound is distinct in its biologic activity from many of the other opium constituents in that it does not exhibit any analgesic activity. Instead, papaverine acts as a nonspecific spasmolytic agent. As such, it has found... 

Papaverine is an opium alkaloid initially isolated in the mid-1800s. It relaxes smooth muscle and is a potent vasodilator. As such it is used to dilate pulmonary and other arteries. It is therefore sometimes of use in the treatment of angina pectoris (usually caused by partial blockage of the coronary artery), heart attacks and bronchial spasms. 

Papaverine Papaverine, molecular formula C20H21NO4, is an isoquinoline alkaloid isolated from poppy seeds Papaver somniferum, family Papaveraceae). This alkaloid is used mainly in the treatment of spasms and of erectile dysfunction. It is also used as a cerebral and coronary vasodilator. Papaverine may be used as a smooth muscle relaxant in microsurgery. In pharmaceutical preparations, papaverine is used in its salt form, e.g. hydrochloride, codecarboxylate, adenylate and teprosylate. The usual side-effects of papaverine treatment include polymorphic ventricular tachycardia, constipation, increased transaminase levels, hyperbihr-unemia and vertigo. 

Following the isolation of morphine by Serturner in 1805 further alkaloids were isolated from opium, for example narcotine in 1817, codeine in 1832, thebaine in 1835 and papaverine in 1848. 

Opium contains more than 20 distinct alkaloids. In 1806, Sertiirner reported the isolation of a pure substance in opium that he named morphine. The discovery of other alkaloids in opium quickly followed that of morphine (codeine by Robiquet in 1832 and papaverine by Merck in 1848). By the middle of the 19th century, the use of pure alkaloids rather than crude opium preparations began to spread throughout the medical world. 

The isolation of morphine from opium and the recognition of the significance of its physiological effects by F. W. A. Sertiirner in 1803-1817 as well as the first definition of the term alkaloid by Meissner in 1819-1821 have led to a rapid progress in the research of alkaloids (1). In the beginning of the past century, much attention was paid to the cultivated poppy plant Papaver somniferum L., which has been used since time immemorial in popular medicine. Of the so-far known 41 opium alkaloids, only morphine, codeine, and papaverine have found... 

Papaverine (6,7,3, 4 -tetramethoxy-l-benzylisoquinoline) was isolated for the first time by Merck (35) from opium. In 1914, Pal (36) demonstrated on animals in vivo that papaverine decreases the tonus of the smooth muscle without affecting its natural mobility. It is a... 

Papaverine dehydroepiandrosterone-3-monophosphate (151) had a much more rapid coronary vasodilator action on the isolated cat heart than papaverine the effect of papaverine was, however, of longer duration. Both compounds inhibited histamine bronchospasms. The spasmolytic effect of papaverine dehydroepiandrosterone-3-mono-phosphate on histamine-induced contractions of the small intestine of guinea pigs was twice as strong as that of papaverine but less toxic than papaverine. 

Administration of papaverine along with trichloroisobutyl alcohol and acetylbromodiethylacetylurea increases the effect of the latter two substances (333). In mice, small doses of papaverine reduce the convulsive effect of procaine not however the lethal dose (334). Papaverine inhibits contractions of excised muscles induced by adenosine derivatives (335). j8-Phenylisopropylamine in relatively high concentration increases the tonus of the vascular musculature of the surviving isolated rabbit aorta. This effect was inhibited by papaverine (336). The effect of papaverine on respiration, blood pressure in dogs and cats, on isolated vessels, on the intestine in situ and in vitro as well as its toxicity in rats was not affected by Nalorphine (337). Premedication... 

Takatonine (5,6,7,4 -tetramethoxy-l-benzylisoquinoline) had a weak atropine-like and papaverine-like effect (370). Its spasmolytic activity was determined on isolated smooth muscle preparations of guinea pig ileum and mouse small intestine. 

Cryptopine was isolated by Smiles (579) from opium in 1867. Its effect (580) is in many respects similar to that of papaverine and berberine. In dogs it produces hypotension, inhibition of cardiac activity, stimulation of respiration, inhibition of faradization of the vagus, and decrease in the oculocardiac reflex in rabbits, it produces relaxation of the skeletal muscle (581). For guinea pigs the LD100 s.c. was found to be 160 mg/kg (582). Mercier el al. (583, 584) reported the effect of cryptopine on the intestine, the nervous system, blood pressure, cardiac activity, and respiration to range between that of papaverine and berberine. 

Narcotine was isolated by Derosne (592) and Robiquet (593) from opium. It has a mild antitussic and a relaxant effect on smooth muscles (similar to those of papaverine). The relaxant effect is about ten times smaller than that of papaverine (594-597). LaBarre and Plisnier (598, 599) found that narcotine is a better antitussic than codeine. j8-Narcotine proved to be much more effective than a-narcotine (600) the effect of the N-oxides of the two isomers was more marked than that of the base. /3-Narcotine N-oxide was much more effective than dihydrocodeine. Those substances did not increase the analgesic effect of morphine. Contrary to codeine they did not cause obstipation (601). The therapeutic dose of the hydrochloride is 25-50 mg three times daily for adults and 25 mg three times daily per os for children. For the effect of narcotine upon the cough reflex and upon the bronchial muscle, see (602-613). 

The non-specific tritiation of papaverine ha been described,13 as have methods for the detection of the alkaloid in body fluids.1415 The effects of papaverine on the biochemical fate of thymidine phosphate in the thymus,16 on cyclic AMP and the uptake of calcium in isolated pig auricle,17 on the monosynaptic reflex,18 on the L-DOPA-influenced secretion of GH and PRL,19 on cerebral blood flow,20 and on longitudinal smooth muscle21 have been studied, as have the /3-receptor-stimulant... 

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