Further elements of structural specificity in potentiation and blockade of excitable tissue preparations by aryl esters of tropine and ψ-tropine. III

Abstract The diphenylacetate, o -chlorophenylacetate, m -chlorophenylacetate, p -chlorophenylacetate, and p -tolylacetate esters of tropine and pseudo tropine have been studied in assorted roles as in vitro inhibitors of the acetylcholinesterase-acetylcholine system, as blocking agents on the single node of Ranvier in frog sciatic nerve and on the phrenic nerve-diaphragm preparation from the rat, and as intravenously administered toxins in the mouse. Considerable evidence for stereospecificity in the drug-tissue receptor interactions produced by any isomeric pair of esters (tropine vs. ψ-tropine derivatives) has been amassed. Specific findings of interest include: 1. 1. The entire series of esters functions in the weak-to-moderate category of AChE inhibitors, with no striking instances of isolated potency. 2. 2. These esters are very potent blocking agents on the single node of Ranvier, producing powerful depression of the action current amplitude and elevation of the threshold voltage requirement at bathing concentrations of 1 m M and below. A striking exception to this behavior is afforded by the p -chlorophenylacetate esters III and III-ψ which display no blocking potencies at low concentrations, but instead produce tiny increases in action current at high (20 m M ) concentrations. 3. 3. On the rat phrenic nerve-diaphragm, the esters generally evoke striking potentiation of the muscle twitch response via either the direct or indirect stimulation pathways, at low (10 −5 to 10 −4 M ) concentrations, followed by an overriding blockade of twitch response as the concentration level is raised. Again, the p -chloro ester III is unique in the series in displaying no potentiating action, and a twitch blockade response (direct stimulation pathway) which is partially alleviated by further increase in concentration of agent. Compound III-ψ shares in the latter behavior. 4. 4. In the intact mouse and cat via the intravenous route of administration, these agents are potent convulsants with additional peripheral involvement. The tropine analogs III and IV are respectively more potent than their pseudo isomers, and in a further demonstration of ordered specificity with the chlorophenylacetate esters in both the tropine and ψ-tropine series, the positional isomerism of the chloro group on the ring furnishes the potency sequence para > meta > ortho. These findings are discussed in terms of possible modes of drug-chemoreceptor interaction in the biologic preparations studied.