Contribution of aryl groups to toxic interactions at chemoreceptors: 3-tropanol phenylacetates and their hexahydro derivatives as toxic agents

Abstract

The new cyclohexylacetate esters of tropine and ψ-tropine have been studied as toxins by the intravenous route in intact mice and cats, as twitch-potentiating agents on the rat phrenic nerve-diaphragm preparation, and as inhibitors of the acetylcholinesterase-acetylcholine system. In sharp contrast with their phenyl ester analogs, the cyclohexyl esters show an abrupt loss of capability to evoke stereospecific responses from chemoreceptor systems in the rat and mouse tissues, and yet display absolute levels of activity equivalent to those of the phenyl ester in the weaker ψ-tropine series. With the acetylcholinesterase system studied as a key nerve enzyme, the cyclohexyl esters show exactly inverted behavior in the sense that they are highly stereospecific with respect to their inhibitory potencies (ψ-tropine>tropine ester), and each cyclohexyl ester is significantly stronger as a reversible inhibitor than its phenyl analog. These results are interpreted in terms of possible modes of functional interaction between these esters and the chemoreceptors controlling the responses of the tissue and enzyme systems studied.