Curarizing agent

A decrease in stability is often a desirable modification. For example, succinylcholine (suxamethonium 3.25) — a neuromuscular blocking agent used in surgery — has a self-limiting activity, since the ester is hydrolyzed in about 10 minutes, preventing the potential for overdose, which could be fatal with more stable curarizing agents. 

Tubocurarine (I) and the various synthetic curarizing agents such as succinylcholine (LXII) have two quaternary nitrogen atoms set some distance apart. The foregoing experiments allow the calabash curare alkaloids to be placed in the same class of compounds. 

The remarkable curariform activity of the Erythrina alkaloids has been discussed in earlier volumes of this series and a review has been published (41). More recent comparison of the activity of dihydro- -erythroidine with standard curare agents such as [Pg.513]

A large number of alkaloids have been converted to quaternary salts and examined pharmacologically. The quaternary derivatives of certain bis-benzylisoquinoline alkaloids, which are closely related structurally to one class of curare alkaloids, are potent curarizing agents. Quaternary salts of cinchona alkaloids are effective and have been used in clinical investigations. Quaternary salts of many other alkaloids have been shown to exhibit curariform activity. 

Toxiferine I is the most physiologically active alkaloid knoAAm and has a nearly constant potency in all species. It paralyzes frogs, mice, rabbits, cats, and dogs in doses of 0.003 to 0.009 mg./kg. it is at least 15 to 30 times as potent as d-tubocurarine. Toxiferine VI and toxiferine XI are also potent curarizing agents with about 20 times the actiAuty of d-tubo-curarine in the rabbit head-drop test. 

In searching for possible useful curarizing agents as well as for clues to the structures of the calabash and toxiferine alkaloids, a number of quaternary salts of open and closed carboline-type compounds have been examined. Some of these compounds which are possible open-chain fragments of the toxiferines, are indicated by formulas IX-XVIII. 

Quinine has long been known to exert a weak curare-hke action. Rosen-stein (102), applying the premise that onium ions are responsible for curariform activity, showed that quaternary derivatives of quinine and cinchonine have lissive activity. Harvey (103) examined quinine methochloride extensively and found it to be effective orally and to produce in cats a sequence of events similar to that produced by curare. A number of quaternary derivatives of the cinchona alkaloids have been evaluated as curarizing agents the results are summarized in Table 4. 

The action of Mytolon chloride (56, 124) appears to have a greater resemblance to that of d-tubocurarine than does that of decamethonium. It has anticholinesterase activity, and in large doses it inhibits parasympathetic ganglia. It is the most potent of the synthetic curarizing agents. 

Changeux, J, P. (1966). Responses of acetylcholineslcra.se from Torpedo marmorata to salts and curarizing agents. Mol Pharmacol 2,369-392. 

The most potent curarizing alkaloids have little effect on blood pressure (in cats), with some exceptions. Toxiferine (48) at a dose of 2 mg intravenously produced paralysis for 50-160 min in a 70-kg human and is probably the most useful specific curarizing agent. The LDioo of toxiferine i.p. is 0.03 mg/kg. Toxiferine binds to the acetylcholine receptor (Wink, 1993). There is no depression of blood pressure, no histamine liberation, and an absence of bronchoconstriction. The diallyl Zjw-nor-derivative has more reproducible activity and is shorter-acting (Cordell, 1981). 

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