Notes - Nα, Nα Dimethylhistamine, Hypotensive Principle in Casimiroa edulis Llave et Lex

The Journal of Organic Chemistry
1958.0

Abstract

The seeds of Casimiroa edulis Llave et Ley., a tree growing in Mexico and Central America, have been used in native medicine as a hypnotic and Ramirez and Rivero3 have reported that an extract of the seeds is used clinically in insomnia in hypertension; deLille4 found that intravenous administration of such extracts produced a marked decrease of blood pressure in dogs, and that the material was toxic in higher doses.A number of chemical investigations of the seeds of Casimiroa edulis have been reported.5,6,7 About a dozen compounds have been isolated, including known coumarins, furanoquinoline alkaloids, and flavones, and some of as yet unknown structure. It was suggested that N-benzoyltyramine might be responsible for the pharmacological activity of the plant6 but no details were given.The hypotensive action of an extract of Casimiroa edulis seeds prepared in this laboratory has been confirmed by Dr. C. A. Stone, of the Merck Institute for Therapeutic Research, West Point, Pa. He found, also, that this effect was not obtained if an antihistamine was also administered, indicating that the hypotensive agent was histamine or a histamine-like compound.Paper chromatographic analysis of a crude extract of Casimiroa edulis seeds by the method of Ames and Mitchell7 showed that histamine itself was absent. However, at least two other compounds were found which gave positive reactions to the Pauly reagent (diazobenzenesulfonic acid), an agent which gives fairly characteristic reactions with imidazoles. Separation of the imidazoles from the crude extract was then effected by the method of Koessler and Hanke.8 Eventually, a pure compound was isolated as its hydrochloride and its picrate; it was identical with Nω,Nω-dimethylhistamine which had been produced synthetically;9 yield of pure compound from seeds was 0.05%. The search for the second compound which gave a positive reaction to Pauly's reagent is being continued.According to Huebner, Turner, and Scholz, Nω,Nω-dimethylhistamine acts pharmacologically much like histamine,9,10 in causing a marked lowering of the blood pressure of animals. Apparently, at least part of the pharmacological activity of Casimiroa edulis seeds may be attributed to the presence of Nω,Nω-dimethylhistamine. As far as we know, previously this compound has been found in nature only in the sponge Geodia gigas,11 and in this case it was not fully characterized.

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