Curare

General types of physiological functions attributed to quaternary ammonium compounds are curare action, muscarinic—nicotinic action, and ganglia blocking action. The active substance of curare is a quaternary that can produce muscular paralysis without affecting the central nervous system or the heart. Muscarinic action is the stimulation of smooth-muscle tissue. Nicotinic action is primary transient stimulation and secondary persistent depression of sympathetic and parasympathetic ganglia. 

The early stmctural evideace, physical properties, and aromaticity of isoquiaoline have been discussed at the beginning of this article. Two additional trivial names are encountered occasionally 2-benzaziae and leucoline. The widespread occurrence of this stmcture ia such important alkaloids as those found ia cactus, opium, and curare has created a long-standing iaterest ia its syathesis and properties (4). 

Other Lethal Agents. There are a number of substances, many found in nature, which are known to be more toxic than nerve agents (6). None has been weaponized. Examples of these toxic natural products include shellfish poison, isolated from toxic clams puffer fish poison, isolated from the viscera of the puffer fish the active principle of curare "heart poisons" of the digitaUs type the active principle of the sea cucumber active principles of snake venom and the protein ricin, obtained from castor beans (See Castor oil). 

Anhalonidine is not so active and resembles pellotine in action. In frogs it produces a type of narcosis or paresis, followed by a phase of increased excitability. Larger doses have a curare action. On mammals the action is slight. 

Canadine is bitter and in small doses causes drowsiness and depression. In large doses it gives rise to transient excitement succeeded by depression and paralysis of the central nervous system. Its injection is followed by violent peristalsis with diarrhoea. It is said to have no effect on the blood pressure. The pharmacological action of canadine a- and -meihochlorides was examined by Laidlaw, who found both to have the curare-like action common to ammonium bases, the -isomeride being the more active the relative activities of the four optically active forms are given as h da. ip dp = 1 Q 2 28. 

Bebeerine and its allies (p. 363) are also derived from menispermaceous plants, but as their botanical source needs attention in some detail, and in view of their importance as close associates of the curare alkaloids, they are dealt with separately at the end of this section. 

These results show that bebeerine is represented by (I Rj = R3 = H and Rj = R = Me). See also curine (Z-bebeerine), dealt with as a curare alkaloid (p. 374). 

Of these authenticated species, Chondrodendron candicans and C. tomento-sum have been examined by King (pp. 364, 376) and the results of work by Wintersteiner and Duteher and by King on curares described as made from C. tomentosum are given below. 

According to Folkers and Unna, the Peruvian ehazuta curare (bamboo type) is made from C. tomentosum R. and P., Annona ambotay Aubl., Aristolochia rumicifolia Mart, and Zucc. and an unidentified plant which is neither a menisperm nor a Stryehnos. Of these four the first was... 

According to-Vellard, a Strychnos sp. similar to S. medeola is used by the Nambikwaras. Brasil, Campos and Kuhlmann have mentioned three S. American species of Strychnos, viz., S. diplinerva, S. off. albiflora Prog and S. brevifolia A.D.C., in which, using extracts of the roots in comparison with Tecuna curare, they have found curarising activity by pharmacological tests in rabbits. 

By fractionation of an extract of the bark of Strychnos lethalis Barb., Carneiro has obtained two products, strychnolethaline, C22H27O4N, and curalethaline, CjgHjiOjN, which he has also isolated from samples of curare. 

In view of increasing interest in the medical applications of curare attention is being given to the elimination of inert material and the provision of a more uniform product. Of primary importance in this... 

Three kinds of curare have appeared in European commerce, distinguished by the kind of container in which they are packed. 

Para, Tube or Bamboo Curare. This variety was packed in sections of bamboo, but this almost traditional information needs modification since tube curare became a commercial article. It is now a viscous, solid or even powdered extract, exported in sealed tins. In view of the relationship established between bebeerine, curine, and tubocurarhie, the active alkaloid of this variety of curare, the suggestion was made, first by Spath, Leithe and Ladeck, and more definitely by King that its botanical source should be sought among the Brazilian Menispermaceae, and as shown later the search for the source of the d-tubocurarine found in this variety of curare has been narrowed down to Chondrodendron tomentosum, or possibly a closely related species liable to be confused with it. 

Gourd or Calabash Curare. This type, exported in small gourds, is said to be made from Strychnos toxifera Schomb., and this was confirmed by King, who isolated from botanically authenticated material collected in British Guiana, an amorphous, quaternary alkaloid indistinguishable from curarine prepared from gourd curare, and Wieland et al. have isolated from this species alkaloids which they have also found in this type of curare. Other Strychnos spp. from the same territory examined by King contained alkaloids, but not of the curarine type. 

Curare was first examined by Roulin and Boussingalt, who isolated a syrupy body, which they named curarine much later a similar substance was obtained by Buchner, - and in 1865 Preyer announced that he had obtained curarine and its salts in a well-crystallised condition, and by analysis of the platinichloride, ascertained its composition to be C10H35N. Sachs - was only able to obtain an amorphous alkaloid, to which he assigned the formula CigHjjN. The work of Boehm explained to some extent these discrepant results he examined all three varieties and showed that they differed in composition, and that the isolation of the various curarines as single substances required special processes. 

Alkaloids of Paka, Tube, ok Bamboo Curare, From this variety. 

Alkaloids of Chondrodendron tomentosum. Butcher has examined a curare prepared by Indians of the Upper Amazon, in which the only plant used was Chondrodendron tomentosum, Ruiz and Pavon. From it he isolated the known alkaloids, d-tjochondrodendrine (p. 365), d-wochondro-... 

These results seemed to establish with certainty that the active component of tube curare is derived from Chondrodendron tomentosum, but the matter again became doubtful when King reported that in the stems of a carefully authenticated specimen of the plant, collected at Tarapoto in Peru, he had found 1-curine and Z-tubocurarine chloride. This is the first recorded natural occurrence of the latter and seems to indicate either that the alkaloidal components of the plant are not constant in character, or that the botanical description of Chondrodendron tomentosum covers two species containing the dextro- and Icevo- quaternary alkaloids respectively. 

Alkaloids of Pot Curare. This variety of curare is a dark brown, comparatively dry extract. According to Boehm, it contains protocurine, colourless hair-like needles, m.p. 306° (dec.), a base of low toxicity and yielding crystalline salts. A second alkaloid of similar type is protocuridine prisms, m.p. 274-6°, sparingly soluble in all ordinary solvents. The poisonous constituent is protocurarine, a red powder, easily soluble in water, and giving characteristic colour reactions with nitric acid and with oxidising agents in sulphuric acid, this latter reaction indicating a Strychnos spp. as a possible botanical source. 

The quaternary fraction of pot curare, after the removal of some neoprotocuridine, was separated into a portion salted out by sodium bicarbonate, and a portion not so precipitated. The latter was fractionated on a plan described in the original, the most active product obtained being an amorphous iodide with a paralysing dose of 1- 5 mg. per kilo frog. This iodide was phenolic, gave the Millon reaction, but no strychnine-like reaction with bichromate and sulphuric acid. No crystalline product could be isolated, but on complete methylation certain of the fractions yielded crystalline methiodides as follows —... 

These results indicate that this specimen of pot curare was of meni-spermaceous origin. 

Alkaloids of Goukd ok Calabash Curare. The toxic constituent of this form, as prepared by Boehm, was an amorphous curarine to which the formula C gHjgONj was assigned. Gourd curare has been investigated in recent years by Wieland et aZ. and by Schmid and Karrer. ... 

The process of isolation finally adopted by the former authors consists in precipitating as reineckates the water-soluble bases contained in a methyl alcoholic extract of the curare. The mixed reineckates are further purified, by solution in acetone and precipitation with water as often as may be necessary. The product so cleaned represents the bulk of the biological activity of the crude drug the mother liquors may contain curine (p. 374), which indicates a menisperm as one of the components of such curares. The mixed reineckates are then fractionated chromato-graphically over alumina and the components isolated as chlorides by the use of silver sulphate and barium chloride in succession. This process has been modified in detail by Schmid and Karrer, who have also found that with their curare, the more soluble reineckate fraction includes less potent quaternary alkaloids. 

The material first used by Wieland et al. was gourd curare from the middle Orinoco district, near Urbana, in Bolivar State, Venezuela, but in the fomth paper (1941) results are recorded for curares from Colombia and Venezuela, for which more precise details of origin are not available and there is considerable difference in the nature and quantity of the alkaloids in the various samples used. An examination has also been made of the bark of Strychnos toxifera, and one of the alkaloids (toxiferine II) it contains has been found in some of the curares examined. In all, ten alkaloids have been obtained and characterised and, with the exception of curine, they are all of quaternary type. They are named toxiferine, dihydrotoxiferine, or calabash-curarine (shortened to C-curarine in practice) according to type, and the variants within the type are distinguished by numbers, or numbers and letters, e.g., toxiferine I, toxiferine Ilb. 

Calabash curare, probably from the middle Orinoco region, has also been investigated by Karrer and Schmid,who have isolated eight new alkaloids in addition to Wieland s C-curarine I. 

The following three products were obtained by Wieland et al. from the early samples of curare from Urbana. 

Calabash-curarine I. This alkaloid was first named toxiferine (1937), as it was expected to be found in Strychnos toxifera bark when this bark yielded a different alkaloid, for which the name toxiferine was more appropriate, the name of the curare alkaloid was changed. Crystalline salts have been prepared of which the chloride, CjoHjaONjCI or HjO,... 

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