124 CHOLINE 



(This expression is to be preferred to the older term "nicotinic," to avoid 

 confusion with the effects of nicotinic acid, now a product of therapeutic 

 importance.) Curare, a powerful alkaloid derived from several South Ameri- 

 can species of Strychnos, acts as blocking agent on skeletal muscles and 

 autonomic ganglia, causing muscular weakness ending eventually in paral- 

 ysis as the muscle becomes completel}^ flaccid. Choline and other quater- 

 nary ammonium salts in higher concentrations have a "curariform" effect. 



Efforts to establish clearly the distinction between the muscarinic action 

 (peripheral effects on glands and smooth muscle cells) and the nicotine-like 

 action (on ganglion cells and skeletal muscles) evoked much study of the 

 esters of choline and of related phosphonium, arsonium, stibonium, and 

 sulfonium bases. 



Hunt and Taveau^' ^ reported upon the circulatory effects and relative 

 toxicities of a large series of choline derivatives. Substitution of the hydro- 

 gen atom of the alcoholic OH group by acid radicals usually increases the 

 physiological activity, from 500 to many thousand times, depending upon 

 the substituent and the particular response observed.^' ^ Acetylcholine, for 

 example, is about 100,000 times more active than choline in causing a fall 

 in blood pressure. Replacing the hydroxyl group by a carboxyl (betaine) 

 leads to a product which is practically inert physiologically. Acetyl-;S- 

 methylcholine (mecholyl) resembles acetylcholine except that it produces 

 practically no nicotine-like action. Carbaminoylcholine (carbachol, doryl, 

 lentine), on the other hand, has a greater nicotine-like effect than acetyl- 

 choline.* 



In comparison with many of its esters and many other quaternary am- 

 monium compounds the toxicity of choline is relatively low. Given as 

 chloride or citrate by mouth, choline has very low toxicity; it is consider- 

 ably more toxic by subcutaneous, intraperitoneal, or intravenous injection. 

 The relatively low (acute) toxicity of choline chloride may be illustrated 

 by a statement of Mott and Halliburton^ in 1899 that "We have never 

 succeeded in killing an animal by injection of choline or choline hydro- 

 chloride." Others had succeeded, however. In 1885 Boehm^" found that 

 0.05 g. of choline chloride injected subcutaneously would kill a small frog, 

 and 0.1 g. a large one. 



The minimum lethal dose, so-called, of choline chloride, for rabbits was 



' R. Hunt and R. De U. Taveau, Brif. Med. J. II, 1788-1791 (1906). 

 5 R. Hunt and R. De M. Taveau, Hyg. Lab. Bull. (U. S.) 73 (1911). 

 15 H. H. Dale, J. Pharmacol. Expil. Therap. 6, 147-190 (1914). 



7 G. A. Alles, Physiol. Revs. 14, 276-307 (1934). 



8 H. Molitor. J. Pharmacol. Exptl. Therap. 58, .337-360 (1936). 



9 F. W. Mott and W. D. Halliburton, Trans. Roy. Soc. (London) B191, 211-267 

 (1899); see p. 223. 



1" R. Boehm, Arch, exptl. Pathol. Pharmakol. 19, 87-100 (1885). 



