Potency convergence and crossover in tertiary vs. quaternary tropine amino esters

Abstract

A series of potency comparisons on functional interactions between tissue chemoreceptors and the p-tolylacetate esters of tropine (II), and tropine methiodide (I), has disclosed an interesting and unexpected element of convergence in tertiary-quaternary amine structure vs. bioactivity relationships. The quaternary amino ester I displays a surprising ability to penetrate membrane barriers to excitable tissues and the blood-brain barrier, approaching and at times even exceeding that of its tertiary parent (II) in potency of a given chemical excitation, amplification, or blocking action. The tertiary and quaternary amino esters are virtually equipotent with respect to central toxic actions in mice and cats, in reversible inhibition of the in vitro acetylcholinesterase-acetylcholine system, and in weak amplification of twitch tension in the cat nerve-muscle soleus preparation under burst electrical stimuli. The quaternary ester exceeds the tertiary in degree of isometric twitch amplification evoked from the rat phrenic nerve-diaphragm preparation receiving burst stimuli via nerve, but the potency sequence is reversed (II>I) with the isotonic preparation receiving single, spaced electrical stimuli via the nerve. Finally, the tertiary ester excels over the quaternary in contractural action on the denervated cat gastrocnemius-soleus preparation and in blockade of the single node of Ranvier in medullated nerve fibers. These findings are interpreted in terms of transitional physical characteristics of a quaternary ammonium function embedded in the tropine fused-ring structure. The charge field generated by the N + atom, which would normally be repelled by potential barriers emanating from (+)-charged loci in biological membranes, can apparently be lowered by insulating properties of the tropine carbocyclic cage to the point of near similarity with the field characteristic of the protonated tertiary amine structure.