Curare derivatives

For the past 40 and more years, a modified form of ECT has been standard, involving sedation with a short-acting barbiturate, muscle paralysis with a curare derivative or similar drugs that prevent activation of the muscles of the body, and artificial respiration with oxygen. The purpose... 

In large doses, injected intravenously, it would bum and hurt horribly, because it s a salt and because it instantly throws off the chemical balance of the blood with which it comes into contact. It makes all muscles lock up in extreme contraction that would hurt unbearably. It wouldn t get to all muscles when a prisoner is being killed with it, however. Since the heart is a muscle and it pumps the blood -- the minute that massive dose of potassium salt hits the heart, one would be history and that would be as far as it would travel. "In lethal injection, three chemicals are used to kill. First, sodium pentothal (its trade name) or thiopental sodium (its chemical name). Then one minute later they inject pavulon. One minute later the potassium chloride. Pentothal is a short acting barbituric acid (barbiturate used in anaesthesia) and is commonly called "truth serum" as it s used in narcoanalysis. It knocks one out. It s a hypnotic. Pavulon is a curare derivative which locks up the lungs so one can t breathe. 

In the 1940s and early 1950s, muscle relaxants were introduced, firstly with curare (derived from the original South American Indian poison studied by Claude Bernard 100 years before) and then over subsequent decades a whole series of other agents. Curare, in the form of tubocurarine, was first used in clinical anaesthesia in Montreal in 1943 by Harold Griffith (bom 1894) and Enid Johnson. In 1946, T.C. Gray first used Curare in Liverpool in the UK The road lies open before us and. .. we venture to say we have passed yet another milestone, and the distance to our goal is considerably shortened . ... 

Most curares derived from Strychnos species in South America are known as calabash curares because they are stored in a calabash or small gourd. Curares of this type are regarded as the most paralytic natural or synthetic neuromuscular blocking agents. At least seven alkaloids have been isolated that are more active than fi -tubocurarine (see Chapter 32). For example, C-toxiferine (48) is about 10 times as active, and C-alkaloid G (49) and E (50) are 100 times more active, being active at 1 fxg per kg (Cordell, 1981). 

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 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. 

Curare is a generic term for various South American arrow poisons. Curare has been used for centuries by the Indians along the Amazon and Orinoco rivers for immobilizing and paralyzing wild animals used for food. Preparations of curare are derived from Strychnos species, which contain quaternary neuromuscular alkaloids like tubocurarine. Tubocurarine is a potent antagonist at the nicotinic acetylcholine receptor. 

The nitrogen atom in quinolizidine derivatives behaves as a tertiary amine and hence it can undergo quaternization by reaction with alkyl halides. For instance, berberine derivative 101 was transformed into 102 by treatment with 3-iodopropanol followed by anion exchange. Compound 102 was then transformed into intermediate 103, which was employed as a precursor for the the preparation of bis-ammonium salt 104 (Scheme 10). This compound showed ultrashort curare-like activity in rhesus monkeys <2001JOC3495>. 

Curare and Structure-Activity Analyses of Quaternary Ammonium Derivatives. . 88... 

Curare is the term for plant-derived arrow poisons of South American natives. 

During the 16th century, European explorers found that natives in the Amazon Basin of South America were using curare, an arrow poison that produced skeletal muscle paralysis, to kill animals. The active compound, d-tubocurarine, and its modern synthetic derivatives, have had a major influence on the practice of anesthesia and surgery and have proved useful in understanding the basic mechanisms involved in neuromuscular transmission. 

Si,Si-Dimethyl-Sila-Substituted Derivatives of Polymethylen-bis-Trimethyl-ammonium Compounds with Curare-Like Activity... 

The alkaloid content of curare is from 4% to 7%. The most important constituent in menispermaceous curare is the bis-benzyltetrahydroisoquinoline alkaloid (+)-tubocurarine (Figure 6.48). This is a monoquaternary ammonium salt, and is water soluble. Other main alkaloids include non-quaternary dimeric structures, e.g. isochondrodendrine and curine (bebeerine) (Figure 6.48), which appear to be derived from two molecules of (R)-N-methylcoclaurine, with the former also displaying a different coupling mode. The constituents in loganiaceous curare (from calabash curare, i.e. Strychnos toxifera) are even more complex, and a series of 12 quaternary dimeric strychnine-like alkaloids has been identified, e.g. C-toxiferine (toxiferine-1) (see page 359). 

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. 

One of the most cited examples of important natural-product-derived drugs is the neuromuscular blocker rf-tubocurarine, derived from the South American plant curare, which was used by South... 

The earliest available preparations, made as infusions and concentrated to a syrup by the native people, were designated as calabash (gourd), tubo- (bamboo), or pot (clay pot) curare depending upon the containers in which the drug was packaged. Curare is obtained from the upper regions of the Amazon river, the Orinoco basin, and the eastern slopes of the Ecuadorian plateau. The term curare is derived from the Indian name (woorari, urari) for poison (Grollman, 1962). 

FIGURE 26.1 Left, Chondodendron tomentosum from which curare is derived right, the Amazonian rain forest, the habitat of the plant. 

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. 

The pharmacological properties of P-erythroidine and its dihydro derivative are very similar to those of d-tubocurarine and therefore need not be described in any detail. The two compounds differ from curare in three important respects, namely, less potent paralytic action on neuromuscular junctions, briefer duration of paralysis, and oral efficacy. Indeed, gastrointestinal absorption of the alkaloids is so rapid and complete that the difference between effective oral and subcutaneous doses is rather small. Dihydro-P-erythroidine is longer acting than P-erythroidine and about six times as active. Similar to curare, P-erythroidine and its dihydro derivative are antagonized at the neuromyal junction by anticholinesterases such as neostigmine. 

A sample of Peruvian curare [possibly derived from Chondrodendron toxiferum (Wedd.) Kruk, et Mold. (Menispermaceae)] provided (R,5)-nor-M -chondrocurine (492),... 

Curare has no effect on sensation, consciousness, or pain and it does not enter the CNS (see Chapter 15). Victims injected with many lethal doses of curare will survive with no apparent damage if adequate respiration can be provided for them. Because of this, curare and derivatives of it are used in medicine to produce paralysis during delicate surgical procedures where involuntary or reflexive movement would be disastrous. The anesthetist provides artificial respiration for the patient until curare is eliminated from the body. 

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