Differences in the stereospecificity of closely related compounds; a reinvestigation of the enantiomers of procyclidine, benzhexol and their metho- and etho-salts

Abstract

Abstract The findings of Duffin & Green (1955) that there are very large differences in the stereospecificity of some closely related phenyl-cyclohexylhydroxypropyl compounds have been confirmed, and it has been shown that this cannot be ascribed to any errors attached to the methods for assessing biological activity, or to inadequate resolution of some of the compounds. Measurement of the affinity constants of the compounds for the postganglionic acetylcholine receptors of the guinea-pig ileum showed that the (+)-and (-)-isomers of benzhexol differ only 5·5-fold in affinity whereas the (+)-and (-)-isomers of procyclidine differ at least 375-fold. This big variation in stereospecificity indicates that changes in one part of the molecule markedly affect the binding of the rest of the molecule and the effects are different in the different enantiomers. It is not possible to interpret the difference between the affinity of the isomers simply in terms of the fit, or failure to fit, of one group, such as the hydroxyl, attached to the asymmetric centre. In the five pairs of compounds tested, the stereospecificity was greatest in the compounds with lowest affinity, which is the reverse of what would be predicted from Pfeiffer's rule.