PHARMACOLOGICAL PROPERTIES OF SOME ANTIMETABOLITES OF SEROTONIN HAVING UNUSUALLY HIGH ACTIVITY ON ISOLATED TISSUES

¹ Laboratories of The Rockefeller Institute for Medical Research, New York, New York

In attempts to realize more active antimetabolites of serotonin a series of N-alkylated 5-aminoindoles has been found to possess unusually high potency when tested on isolated tissues in vitro. All of these compounds were derived from the previously described antimetabolite of serotonin, viz., 2-methyl-3-ethyl-5-aminoindole by addition of methyl or other alkyl groups to the amino group. The most active members of the series were 2-methyl-3-ethyl-5-dimethylaminoindole, which was called medmain for the sake of brevity, and its 1-methyl derivative. In the test for antiserotonin-activity using rings cut from sheep carotid arteries medmain and 1-methylmedmain were each about 250 times more active than the parent, unalkylated amine. In the artery test, the other members of the series were more active than previously-known antiserotonins, but were not as powerful as medmain. Medmain was also very active in antagonizing the contracting action of serotonin on isolated uteri of rats. On these tissues, in contrast to the findings in arteries, high concentrations of medmain exhibited a serotonin-like effect. It had thus both pro- and anti-metabolite properties, depending on the concentration. The serotonin-like action of medmain on uterus was antagonized by other antiserotonins, such as 2-methyl-3-ethyl-5-aminoindole and 2-methyl-3-ethyl-5-hydroxyindole. These results were not considered unusual in the light of existing knowledge about the actions of antimetabolites. The contracting effect of serotonin on rat uterus was found to be dependent on the stage of the estrus cycle. It could be demonstrated in virgin rats only during estrus. Medmain, although highly active on these isolated tissues, was found incapable of protecting normal dogs from the pressor effects of serotonin. The reason for this failure was not clear. Medmain injected intraperitoneally into mice called forth convulsions which seemed to resemble the signs of human epilepsy, although no neurological examinations were made to explore this analogy. Neither serotonin nor its methyl ether was found capable of preventing this convulsant action. Several reasons were advanced for thinking that the convulsant action was due to a serotonin-like effect on the central nervous system.

This article has been cited by other articles:

				E. SHAW and D. W. WOOLLEY Some Serotoninlike Activities of Lysergic Acid Diethylamide Science, July 20, 1956; 124(3212): 121 - 122. [PDF]

				V. Erspamer Gramine Derivatives Antagonistic to 5-Hydroxytryptamine (Enteramine) Science, March 11, 1955; 121(3141): 369 - 370. [PDF]