Schönenberger, Helmut and Petter, Alfred and Zwez, W. (1967) Correlations between active substance and receptor in local anesthetics of the N-aminoacyl ephedrine type. Pharmaceutica acta Helvetiae 42 (8-10), pp. 593-603.
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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.
|Additional information (public):||CAN 67:115443 15 Pharmacodynamics 2480-20-8; 2673-32-7; 5042-94-4; 7232-11-3; 7232-12-4; 7232-12-4; 7275-84-5; 7278-68-4 Role: BAC (Biological activity or effector, except adverse), BSU (Biological study, unclassified), THU (Therapeutic use), BIOL (Biological study), USES (Uses) (anesthetic activity of)|
|Institutions:||Chemistry and Pharmacy > Institute of Pharmacy > Retired Professors > Prof. Schönenberger|
|Keywords:||Circulation (N-aminoacyl ephedrine derivs. effect on heart) Nerves (blocking agents for, N-aminoacyl ephedrine derivs. as) Heart (circulation in, N-aminoacyl ephedrine derivs. effect on) Anesthesia (from N-aminoacyl ephedrine derivs.) LOCAL ANESTHETICS MOL CONFIGURATION LOCAL ANESTHETICS EPHEDRINES NERVE EFFECT NERVE EFFECT EPHEDRINES RECEPTOR EPHEDRINES BINDING|
|Subjects:||500 Science > 540 Chemistry & allied sciences|
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Unknown|
|Deposited On:||19 Nov 2010 08:58|
|Last Modified:||19 Nov 2010 08:58|