Effect of sulfur substitution for the noncarbonyl oxygen in hemicholinium-3 and acetyl-seco-hemicholinium-3. Synthesis, biological activity, and structure-toxicity relations. 2

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Abstract
As a continuation of efforts to develop and study inhibitors which act presynaptically on neuromuscular function, S analogues of hemicholinium-3 (HC-3, 1) and acetyl-seco-hemicholinium-3 (AcHC-3, 3) were prepared. In each case S is substituted for the noncarbonyl oxygen in HC-3 (1) and AcHC-3 (3). As expected on the basis of conformational differences between acetylcholine and acetylthiocholine, both of the thio analogues are produced in the seco form and do not cyclize spontaneously or when subjected to aqueous, acidic conditions up to 100.degree. C. Both compounds are stable in aqueous pH 7.4 solutions at 37.degree. C and in slightly acidic D2O solutions for more than 24 h. While thio-seco-hemicholinium-3 (11) is stable in the presence of acetylcholinesterase and butyrylcholinesterase in H2O at pH 7.4, acetylthio-seco-hemicholinium-3 (12) reacts within seconds to form the hemiacetal form of thiohemicholinium-3 (16). Mouse toxicity studies (LD50) indicate that while 12 is approximately as toxic as HC-3 (1) and AcHC-3 (3), 11 is 226 times less toxic. As in the studies with 1 and 3, mice were protected from 11 by choline and slightly by neostigmine. Almost equal and intermediate protection against 12 was afforded by choline and neostigmine. Structure-toxicity relationships of 1, 3, 11, 12 and 16 are discussed.