346 ON THE TOXICITY OF 



researches of Stockman l and Poulsson 2 that esterification 

 is the essential feature. Neither view is universally true, but 

 both have had an important bearing on the search for substi- 

 tutes for cocaine. A third point of importance which appears 

 to have been established is that the presence of a phenolic 

 hydroxyl confers irritant properties on a substance, and is 

 consequently best avoided. Recently 3 evidence has been 

 brought forward to show that the principle of partition- 

 coefficients plays an important part in the action of local 

 anaesthetics, but so far this view has had no influence on the 

 production of substitutes for cocaine. 



The first substitute of real value was not synthetically 

 prepared, but was isolated from Java coca leaves by Giesel. 4 

 It was shown by Liebermann 5 to break up, on hydrolisation, 

 into benzoic acid and pseudo-tropine, and was termed by 

 him tropacocaine. Its pharmacological action was investi- 

 gated by Chadbourne, 6 who showed that while being a power- 

 ful local anaesthetic it was less toxic than cocaine, and possessed 

 certain actions differing from those of cocaine. As a result of 

 his researches, Liebermann gave to it the following constitu- 

 tional formula : 



Hr\ ri-rj rtTj / 



0\-/ 1^X1 l_/Xi . ' 



-CH CH 2 



Tropacocaine 



The first synthetic substitute for cocaine was obtained as 

 the result of investigations on the pharmacological influence 



1 Pharmac. Journ. (3), xvi. p. 897 (1886) ; Jmtrn. Anal. Physiol, xxi. p. 46 (1886). 



2 Arch.f. exp. Path. u. Pharmak., xxrii. p. 301 (1890). 



3 Gros, Arch. f. exp. Path. u. Pharmak., Ixii. p. 380 ; Ixiii. p. 80 (1910). 



4 Pharmazeut. Zeitung., July 4, 1891 ; quoted by Liebermann and by Chadbourne. 



5 Ber. d. deut. chem. Ges., xxiv. p. 2336 (1891) ; with Limpach, xxv. p. 927 (1892). 

 Brit. Med. Jmirn., 1892, ii. p. 402. 



