A Theory of Anesthetic Action Based upon ~ c e t ~ l c h o l i dCompetition e FRED W. SCHUELER University of Colorado, Boulder, Colorado
I
T HAS been known for some time that compounds hav~ngthe structure 0
will generally possess local anesthetic action.' amples of this are the following:
Ex-
and the sulfa drugs. The problem concerning the local anesthetic class of drugs, illustrated above, therefore (if drug competition is assumed) reduces itself to discovering a substance occurring a t the nerve endings and essential for nerve impulse transference which resembles the anesthetic drugs s,@ucturally. Such a substance is exemplified by a~etylcholine.~
It is seen that by replacing the CHa-group by a phenyl group, one obtains a structural type resembling the local anesthetic drugs. Assuming that the local anesthetic drugs may compete with acetylcholine a t the nerve endings, the writer has carried out some simple experiments which, though far from conclusive, do indicate, that further experimentation of a more rigorous nature may show the above hypothesis to be a possible theory for explaining the typical action of the cocaine group of drugs. Adult Yale strain rats, divided into four groups, were injected intraperitoneally as follows:
In all of the above structures the essential features for anesthetic action are the benzoyl group' (the appended p N H 2 groups in I1 and I11 not being essential for anesthetic action) and the carbon chain terminating in the alkylated nitrogen. When one finds in a given set of pharmacologically active substances such well-defined essential structural features, the possibility of drug competition with some substance normally present in the organism is suggested. Competition between two drugs is possible when the two substances have some features in common, e . g., pan~inobenzoicacid
Group I. Controls, received no injections. Group 11. Received cocaine in physiological dosage~.~ Group 111. Received cocaine and acetylcholine each in physiological dosagesa Group IV. Received only acetylcholine in physiological dosage^.^ In each case the rats receiving both acetylcholine and cocaine were freed from symptoms (or these were greatly reduced) possessed by the rats receiving cocaine or acetylcholine separately; i. e., they appeared normal.
' ING,H. R., Trans. Faradey Soc., 39,372 (1943).
J. H., Ann. Reu. Biochem., 4. 311 (1935). GADDUM, Gnraarrn.. T. - 0. AND E. T. FARRIS.Editors. "The Rat in Laboratory Investigation," ~ . + ~ . ~ i p ~ i n &&any, 'cott Chicago, 1942, p. 305.
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