Domer F R, Chihal D M, Charles H C, Rege A B
J Med Chem. 1977 Jan;20(1):59-62. doi: 10.1021/jm00211a011.
As a continuation of our efforts to develop and study inhibitors which act presynaptically on neuromuscular function, sulfur analogues of hemicholinium-3 (HC-3, 1) and acetyl-seco-hemicholinium-3 (AcHC-3, 3) were prepared. In each case sulfur 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 degrees C. Both compounds are stable in aqueous pH 7.4 solutions at 37 degrees 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. It is of interest, however, that 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.
作为我们开发和研究对神经肌肉功能起突触前作用的抑制剂工作的延续，我们制备了半胱氨酰胆碱-3（HC-3，1）和乙酰-裂-半胱氨酰胆碱-3（AcHC-3，3）的硫类似物。在每种情况下，硫取代了HC-3（1）和AcHC-3（3）中的非羰基氧。基于乙酰胆碱和乙酰硫代胆碱之间的构象差异，正如预期的那样，两种硫代类似物均以裂形式产生，并且在高达100℃的水性酸性条件下不会自发环化或环化。两种化合物在37℃的pH 7.4水溶液和微酸性D2O溶液中稳定超过24小时。虽然硫代-裂-半胱氨酰胆碱3（11）在pH 7.4的H2O中存在乙酰胆碱酯酶和丁酰胆碱酯酶的情况下稳定，但乙酰硫代-裂-半胱氨酰胆碱-3（12）在几秒钟内反应形成硫代半胱氨酰胆碱-3（16）的半缩醛形式。小鼠毒性研究（LD50）表明，虽然12的毒性与HC-3（1）和AcHC-3（3）大致相同，但11的毒性低226倍。与对1和3的研究一样，胆碱对小鼠有保护作用，新斯的明有轻微保护作用。然而，有趣的是，胆碱和新斯的明对12提供了几乎相等的中间保护作用。讨论了1、3、11、12和16的构效关系。
