Absolute configuration and parasympathetic action: Pharmacodynamics of enantiomorphic and diastereoisomeric esters of β-methylcholine

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Abstract
The parasympathomimetic and atropine-like actions of enantiomorphic esters of β-methylcholine and various esters of choline or β-methylcholine containing an asymmetric centre in the acid moiety have been studied. The potent parasympathomimetic drugs have a configuration identical with that of muscarine, suggesting a close affinity with the receptor. There is a gradual change from agonist to antagonist with increasing molecular size of the acid moiety, antagonism beginning with the butyric ester. Optimal affinity as a mimetic in the lower homologues is obtained with the acetic ester. Maximum affinity as an antagonist is obtained with the ester of the bulky hexahydrobenzilic acid. The configuration of the choline part is irrelevant for high atropine-like potency in the compounds derived from β-methylcholine. Clear differences in affinity are found, however, between stereoisomers of potent antagonists containing an asymmetric centre in the acid moiety, provided the asymmetric carbon atom does not bear isosteric groups. It is concluded that the atropine-like agents, although being competitive antagonists of the parasympathomimetics at best cover the agonistic receptor area only partially.