Curare based

Curares based on Menispermaceae predominate in the Pemvian Amazon region (in the area bounded by the rivers Napo, Marahon, and Ucayali) mixed Logania-ceae/Menispermaceae curares are found chiefly in the area covered by the middle reaches of the Brazilian Amazon and its tributaries and Strychnos curares come principally from the region between the Orinoco in the north and the Negro and lower reaches of the Amazon in the south (Vellard 1965, 1973). There is, however, evidence that mixed curares were also made in Guyana (Moody 1965, Snedden et al. 1970).. ... 

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. 

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 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. 

C-Toxiferine II. This base was obtained from curares from Urbana and Caracas, sometimes accompanied by toxiferine II (see below), and was isolated by a special method as the chloride, C20H25ON2CI, [a] -f- 72-1° (H2O). The picrate forms hexagonal prisms, m.p. 215° (dec.). 

The curare alkaloids, which are constituents of arrow poisons used by South American Indians, are complex bases which usually contain one or more quaternary centers. They act at the neuromuscular junction, preventing muscles from responding to nerve impulses or to acetylcholine, and they are used to secure muscular relaxation during surgery. 

A frequently cited example of an important natural-product-derived drag is the neuromuscular blocker d-tubocurarine, derived from the South American plant curare, which was used by South American Indians as an arrow poison (see Chapter 26). Tubocurarine led to the development of decamethonium, which, although structurally dissimilar to tubocurarine, was nevertheless synthesized based on the then prevalent presumption that tubocurarine contained two quaternary nitrogens. Similarly, synthetic local anesthetics, such as lidocaine, benzocaine, and dibucaine, were synthesized to mimic the nerve-blocking effect of cocaine, a natural alkaloid obtained from the leaves of Coca eroxylum, but without the adverse side effects that have led to its abuse. 

The beanlike seeds of the trees and shrubs of the genus Erythrina, a member of the legume family, contain substances that possess curare-like activity. The plants are widely distributed in the tropical and subtropical areas of the American continent, Asia, Africa, and Australia, but apparently they are not used by the natives in the preparation of arrow poisons. Of 105 known species, the seeds from more than 50 have been tested, and all were found to contain alkaloids with curariform properties. Erythroidine, from E. americana, was the first crystalline alkaloid of the group to be isolated. It consists of at least two isomeric alkaloids, a and P-erythroidine both are dextrorotatory. Most experimental and clinical study has centered on the b form because it is more readily obtainable in pure state. P-Erythroidine is a tertiary nitrogenous base. Several hydrogenated derivatives of p-erythroidine have been prepared of these, dihydro-P-erythroidine has been studied most carefully and subjected to clinical trial. Conversion of P-erythroidine into the quaternary metho salt (p-erythroidine methiodide) does not enhance, but rather almost entirely, abolishes its curariform activity this constitutes a notable exception to the rule that conversion of many alkaloids into quaternary metho salts results in the appearance of curare-like action. 

These alkaloids were isolated, along with their unsaturated analogs (see Section II,B,4), from Cissampelos ovalifolia D.C., an alleged component of Mac-ushi curare, and characterized in 1970 by chemical interrelation and MS studies. At that time it was shown that the three bases have the same skeleton,... 

The application of the Emde degradation conditions (0.1 N KOH/C2H5OH, H2/Pt) to the quaternary curare alkaloid, mavacurine iodide (VIII/94), led to the so-called e2-dihydromavacurine (VIII/95), a tertiary base, Scheme III/18. Protonation (e.g. HC1/H20) or methylation (CH3I) of VIII/95 led to the trans-annular reaction products, VIII/96 and VIII/97, respectively. The quaternary compound, VIII/96, returns to tertiary VIII/95 (reversible Hofmann elimination) in the presence of base or on tic (silica gel) [55]. 

Many opium-derived and other IQs are psychoactive, the best known being the analgesic, addictive, narcotic, opium-derived morphinan alkaloids codeine and morphine (heroin being the semi-synthetic diacetate of morphine). The tertiary or quaternary amine structural component is important for the activity of some Erytkrina alkaloids and bisbenzyliso-quinolines (notably the major curare component (+)-tubocurarine) as antagonists of the nACh-R involved in neuronal excitation of skeletal muscle. The planar disposition of some polycyclic benzophenanthridines enables intercalation (parallel interleaving) between the base pairs of DNA. A variety of naturally occurring and synthetic IQ compounds are protein kinase inhibitors. 

Russian workers have prepared for pharmacological studies simple carbamates of trachelanthamidine (68) by treatment with the appropriate isocyanate. Some cholinesterase inhibitors based on the standard decamethonium model have been prepared. Decamethylene bistrachelanthamine dibromide (69) showed marked curare-like activity in cats and rabbits. New procedures for the iodometric determination of platyphylline bitartrate and for the colorimetric determination of trichodesmine and incanine in the organs of poisoned animals have been described. 

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