Curare-like

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. 

It has long been known that quaternary ammonium salts can exert a curare-like action, and in recent years much attention has been given to the synthesis and pharmacological testing of such products work on this subject up to 1936 has been reviewed by Ing, and more recently a theoretical discussion of the relationship between structure and action in drugs of this type has been provided by Holmes, Jenden and Taylor.Chase, Lehmann and Yonkmann have compared the action of quaternary salts of quinine with that of -erythroidine hydrochloride and of dihydro- -erythroidine hydrobromide. Quinine ethochloride shows marked curariform action of short duration. ... 

Brucine closely resembles strychnine in action, but is much less poisonous and it also has a more marked curare-like action on the nerve-endings in voluntary muscle. 

This view was supported by the observation that choline on treatment with nitric acid yielded a product having a pharmacological action similar to that of muscarine as known up to that time. Comparison of the natural and artificial products by Bohm showed that the former was much more active than the latter and that its action was antagonised by atropine, whilst the artificial muscarine had a curare-like action on the atropinised frog. Later, Nothnagel investigated the action of... 

In addition to natural muscarine and the so-called choline-muscarine referred to above, two other products have been given names suggesting relationship to muscarine, viz. (1) isomuscarine, Me3N(OH). CHOH. CH2OH prepared by Bode and shown to be toxic, but distinct from muscarine in type of action, and (2) anhydromuscarine (betaine aldehyde) made first by Berlinerblau and later by Fischer and which, according to Voet possesses nicotine and curare-like properties. 

A preliminary report on rauwolscine by Chakravarti indicates that it is a cardiovascular depressant, shows hypotensive action and a relatively high toxicity. Koepfli s rauwolfine produces a fall in blood pressure, and stimulation of respiration in frogs it has a curare-like action. The rauwolfine of van Itallie and Steenhauer has been examined by Hartog and by de Boer, especially in regard to its cardiac action. According to Raymond-Hamet, it reverses the action of adrenaline. 

Qomoma kamassi E. Mey. Alkaloid with curare-like action. (Dixon, Proc, Roy. Soc., 1911, 83B, 287.)... 

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>. 

Barlow RB, Ing HR (1948) Curare-like action of polymethylene bis-quaternary ammonium salts. Br 1 Pharma Chemother 3 298-304... 

Curare-like muscle relaxants quaternary ammonium salts... 

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. 

Atracurium, a curare-like muscle relaxant that is metabolized via an elimination reaction... 

Nicotine affects the nervous system, interacting with the nicotinic acetylcholine receptors, and the tight binding is partially accounted for by the structural similarity between acetylcholine and nicotine. Curare-like antagonists also block nicotinic acetylcholine receptors (see Box 6.7). There are other acetylcholine receptors, termed muscarinic, that are triggered by the alkaloid muscarine. The tropane alkaloid hyoscyamine (see Box 10.9) binds to muscarinic acetylcholine receptors. 

Tubocurarine and the majority of synthetic curare-like compounds contain two or more quaternary nitrogen atoms located approximately 1.0 0.1 mn from each other, which is a necessary condition for this drag to bind with nicotinic cholinoreceptors. 

Unfortunately, paralysis of skeletal muscle attained by using curare-like compounds, in the majority of cases, is not useful for general conditions of spasticity accompanied by the CNS involvement, as well as for local injuries or inflammation. Of course, neuromuscular blockage reduces spasms however, it is accompanied by loss of voluntary movement. 

The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin. Aminoglycosides Cautiously perform coadministration of botulinum toxin type A and aminoglycosides or other agents interfering with neuromuscular transmission (eg, curare-like nondepolarizing blockers, lincosamides, polymyxins, quinidine, magnesium sulfate, anticholinesterases, succinylcholine chloride) because the effect of the toxin may be potentiated. 

Neuromuscular blockade Neurotoxicity can occur. Aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on the neuromuscular junction. 

Dzhakhangirov, F. N. and Bessonova, I. A. 2002. Alkaloids of Aconitum coreanum. X. Curare-like activity - Structure relationship. Chemistry of Natural Compounds, 38(1) 74-77. 

Mecfianism of Action A cinchona alkaloid that relaxes skeletal muscle by increasing the refractory period, decreasing excitability of motor end plates (curare-like), and affecting distribution of calcium with muscle fiber. Antimalaria Depresses oxygen uptake, carbohydrate metabolism, elevates pH in intracellular organelles of parasites. Therapeutic Effect Relaxes skeletal muscle produces parasite death. Pharmacokinetics Rapidly absorbed mainly from upper small intestine. Protein binding 70%-95%. Metabolized in liver. Excreted in feces, saliva, and urine. Half-life 8-14 hr (adults), 6-12 hr (children). 

Receptor interactions were seen at nicotinic and muscarinic receptors. No correlations were found, however, between atropinelike or curare-like actions of these compounds and their protective effects against organophosphate poisoning. 

The cholinesterase inhibitors have important therapeutic and toxic effects at the skeletal muscle neuromuscular junction. Low (therapeutic) concentrations moderately prolong and intensify the actions of physiologically released acetylcholine. This increases the strength of contraction, especially in muscles weakened by curare-like neuromuscular blocking agents... 

In very high doses, aminoglycosides can produce a curare-like effect with neuromuscular blockade that results in respiratory paralysis. This paralysis is usually reversible by calcium gluconate (given promptly) or neostigmine. Hypersensitivity occurs infrequently. 

The sudden absorption of postoperatively instilled kanamycin from the peritoneal cavity (3-5 g) has resulted in curare-like neuromuscular blockade and respiratory arrest. Calcium gluconate and neostigmine can act as antidotes. 

Neurotoxicity. When at least two of the alkyl-substituents are relatively small, all can cause a curare-like (neuromuscular blocking) effect. [1, 2]. Ammonium tends to be the most toxic, followed by sulfonium, and phosphonium (the least toxic). 

Decamethonium, a synthetic drug with potent curare-like activity... 

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