THE TOXICITY AND ANALGETIC ACTIVITY OF SOME CONGENERS OF SALICYLAMIDE

¹ Department of Pharmacology and Experimental Therapeutics, School of Medicine and College of Pharmacy, University of California, San Francisco 22

Eighty-one congeners of salicylamide have been evaluated in rats as to toxicity and ability to elevate the pain-response threshold to pressure stimulus. Most of the agents appear to be central nervous system depressants and some possess pronounced hypnotic properties. The various derivatives studied differ from the parent compound with respect to groups substituted in the benzene nucleus on the amide nitrogen, and/or on the phenolic oxygen. The toxicity and analgetic potency of salicylamide may be decreased or increased by such chemical modifications with generally paralleled effects, but the changes in each effect are not always equivalent. N-methylation, N-ethylation, or N,N-diethylation usually caused an increase in toxicity which was not always accompanied by increased analgetic potency. N--hydroxyethylation and N,N-dimethylation usually resulted in decreased toxicity and potency. Substitution into the benzene ring at position 3, 4, or 5 with phenyl, bromo, hydroxyl, or methoxyl groups generally decreased toxicity and potency. In ring substituted salicylamide derivatives, the effects of chemical modification were not as predictable. For example, with 3-phenylsalicylamide, N,N-dimethyl or diethyl substitution both yielded more potent derivatives than their unsubstituted analogs.

Four compounds have been selected for more extensive study. Compound S2-347, 2-allyloxy benzamide, was found to be about three times as potent as salicylamide, with a comparable activity (LD₅₀/AD₅₀) ratio. Compound S2-426, N,N-dimethyl-3-phenylsalicylamide, was found to be less toxic and more active than salicylamide, with its activity ratio exceeding that of salicylamide by fourfold. Two agents, S2-7, 3-phenylsalicylamide, and S2-62, N-(-hydroxyethyl)-3- phenylsalicylamide were found to have a low order of toxicity and activity ratios greater than that of salicylamide. Both are currently under clinical investigation.

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