Muscle relaxants Curare alkaloids

The chemistry of the muscle-relaxant Strychnos alkaloids has been reviewed several times (255, 264, 266-268) and will not be further discussed here. Table 1.4 records information about the curarizing activity of and the... 

Curare-like muscle relaxants act by blocking acetylcholine receptor sites, thus eliminating transmission of nerve impulses at the neuromuscular junction. There are two acetylcholine-like groupings in the molecules, and the drugs, therefore, probably span and block several receptor sites. The neurotransmitter acetylcholine is also a quaternary ammonium compound. The natural material present in curare is tubocurarine, a complex alkaloid that is a mono-quaternary salt. Under physiological conditions, the tertiary amine will be almost completely protonated (see Section 4.9), and the compound will similarly possess two positively charged centres. 

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. 

The development and use of muscle relaxants, to allow a reduction in the level of anesthesia during surgery, follows entirely from studies of South American arrow poisons (44)and particularly from the isolation by King (45) of pure D-tubocurarine (29) in the 1930s, from tube curare. Another of the South American blowpipe poisons, calabash curare, was used for similar purposes and developed (46,47), to give alcuronium (30) from the alkaloid C-toxiferine 1 (31). Both types of curare paralyze skeletal muscle by a similar mechanism, antagonizing the effect of acetylcholine at the neuromuscular junction (48). 

Such compounds often exhibit chemical and spectral behaviour which is specifically characteristic of the dimeric structure. Also of paramount interest are the specific pharmacological properties of certain of these alkaloids, such as the muscle relaxation action of the curare alkaloids and the anti-leukemia activity of the Vinca alkaloids leurocristine and vinblastine. Such aspects will be discussed in the last two sections of the review. 

Plant extract used by South American Indians to prepare poison arrows. Sold with different names (e.g. Tube-curare) depending on the container used for packaging. Toxicologically active principle is the alkaloid tubocurarine chloride. Muscle relaxant, toxic by respiratory paralysis and hypotension competitive blocker ACh receptor in muscle. 

Historically, Bernard (1851, 1856) demonstrated that curare (from arrow poisons used by South American Indians) blocked nerve impulse transmission at the junction of the nerve and skeletal muscle. It was later shown that many alkaloids, such as morphine, atropine, nicotine, and even strychnine and brucine (the latter two normally causing convulsions), will become muscle relaxants when quaternized by methylation. It soon became apparent that a great many quaternary ammonium compounds qualitatively share the ability to produce neuromuscular blockade. In fact, the onium ion need not be a nitrogen atom. Thus sulfonium (/ 3S+), phosphonium (/ 3P+), and arsonium (/ 3As+) ions have been shown to be curariform , although of lesser activity than ammonium ions. 

In current scientific usage, curare refers only to those C. a. with muscle-relaxing (paralysing) effects, namely the dimeric indole alkaloids with a strychnine skeleton and two quaternary nitrogens. These compounds are extremely poisonous calabash alkaloids E and G cause death by respiratory paralysis and are among the most toxic compounds known. 

Curare is a muscle relaxant drug, originally used as an arrow poison by Amazonian Indians. The traditional curare is prepared by a secret recipe thought to involve a number of plant species (Plotkin 1993). Plant sources of curare include Strychnos castelnaei and species in the Loganaceae family and Chondodendron tomentosum in the Menispermaceae family. Tubocurarine, a benzylisoquinoline dimer, is the major alkaloid in the curare plants. It exhibits paralysing effects on skeletal muscles, and is used as a muscle relaxant in surgical procedures. It controls convulsions caused by the toxic alkaloid strychnine. 

Muscle-Relaxant Activity of the Strychnos Species Associated with Curare and of Their Alkaloids... 

Full understanding is hampered by current deficiencies in our knowledge of the chemical composition of the plants concerned—for tubocurarine has so far only been found in Chondrodendron tomentosum—yet, as demonstrated by the curare formulas given in Section 1.2.3.1, there are curares from regions 2 and 3 that do not have this species as an ingredient, so that their muscle-relaxant activity must be due to alkaloids from other plants, e.g. Abuta (cf. Section 1.4.6.4) or Cur area species. 

Pharmacological evaluation of the curare showed that it contained 22.2% muscle-relaxant alkaloids calculated as ( + )-tubocurarine. 

There is a very extensive literature on the pharmacology of curares and their active principles. The following references will provide an entry into the relevant literature Strychnos-hased curare and associated quaternary Strychnos alkaloids (41, 252, 481-484) Menispermaceae-based curare and associated alkaloids (252, 344, 345, 347, 353,419). It is not possible within the limits of this present Section to do more than briefly consider the toxicity and muscle-relaxant activity of curares and their active principles, as a prelude to Section 1.6 which outlines the development of some modern muscle relaxants. 

As an appropriate finale to the curare story, the role of the poison and its alkaloids in the development of modern muscle-relaxants is outlined. 

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