Correlations between active substance and receptor in local anesthetics of the N-aminoacyl ephedrine type

Abstract

The influence of mol. configuration and of pH on the activity of a local anesthetic was detd. by comparing the activities of the 8 stereoisomers of N-(N,N-dimethylphenylalanyl)ephedrine against the isolated ischiadic nerve of frogs and by detg. the median effective dose (ED50) of each stereoisomer required to slow heart ventricle flow rate in frogs by 50% (after 30 min.). The results were as follows (stereoisomer, minimal blocking concn. in millimoles/l. against the ischiadic nerve at pH 6.35 except where noted, and ED50 in micromoles/l. given): N-(L-N,N-dimethylphenylalanyl)-D-ephedrine (I) 2.0 (pH 7.35), 93.0; N-(D-N,N-dimethylphenylalanyl)-L-ephedrine (II) 4.1 (pH 7.35), 72.0; N-(L-N,N-dimethylphenylalanyl)-L-ephedrine, 11.0, 35.0; N-(D-N,N-dimethylphenylalanyl)-D-ephedrine, 17.0, 62.0; N-(L-N,N-dimethylphenylalanyl)-D-y-ephedrine, 11.3, 96.0; N-(D-N,N-dimethylphenylalanyl)-L-y-ephedrine, 16.8, 78.0; N-(L-N,N-dimethylphenylalanyl)-L-y-ephedrine, 12.0, 200.0; N-(D-N,N-dimethylphenylalanyl)-D-y-ephedrine, 15.2, 102.0. The similarity of the compds. eliminates the possibility that the differences in activity are due to different soly. in the substrate. The different activities of the stereoisomers are attributed to the existence of a stereospecific receptor, possibly a phosphatide. II (const. concn.) in a soln. at pH 6.2 (94% protonated II) was 45% effective for inhibiting the heart ventricle flow rate in frogs but changed in effectiveness as the pH was increased to 8.3 (85% protonated II), i.e., .apprx.42% inhibition at pH 6.8, .apprx.44% at pH 7.3, .apprx.60% at pH 7.9, and .apprx.70% at pH 8.3. Similar, but less pronounced (range of inhibition 30-40%), results were obtained when I was tested at pH 6.2-8.3. Plots of activity against pH are similar in shape but not in magnitude for I and II. The expts. show that hydrophobic binding is important in N-aminoacylephedrine-receptor bonding.