Comparative Physiological Action of Quaternary Ammonium Salts of the Epinephrine Series. ∗

Abstract

The classical studies of Barger and Dale 1 on the relationships between chemical constitution and physiological action of compounds related in structure to epinephrine included 3 quaternary ammonium salts, hordenine methiodide, 3:4-dihydroxyphenylethyl trimethyl ammonium chloride and trimethylaminoacetocatechol chloride. These compounds were found to resemble nicotine, rather than epinephrine, in their physiological actions and the conclusion was tentatively drawn that the relative intensity of these effects paralleled the relative intensity of the sympathomimetic action of the corresponding amino or methylamino derivatives. It became of interest to see if this generalization would hold for other quaternary ammonium salts of the epinephrine group of compounds, since it might be considered to indicate a close similarity in the processes by which nicotine and epinephrine act upon their respective cellular mechanisms.

Sixteen compounds of this type have been synthesized and studied. Their structures may be represented by the general formula, where R is C₆H₅-,

p-HO-C₆H₄-, p-CH₃O-C₆H₄-, p-CH₃COO-C₆H₄-, or m, p-(HO)₂-C₆H₃-; R₁ is H, OH, OCOCH₃ or OCOC₆H₅ and R₂ is H or CH₃.

In general, all of these compounds exert a certain degree of activity resembling that of nicotine, with regard to their central nervous system and circulation effects as indicated by the respiratory and pressor responses in dogs following their intravenous injection. Many of these compounds are intensely active, some more active than nicotine on injecting molecularly equivalent concentrations, and the circulatory effects of almost all these compounds in comparison with their central nervous system effects seem to be relatively greater than observed with nicotine.