Paper
THE 6‐HYDROXYLATION OF TRYPTAMINE DERIVATIVES: A WAY OF PRODUCING PSYCHOACTIVE METABOLITES
Published Jan 1, 1962 · S. Szára, E. Hearst
Annals of the New York Academy of Sciences
44
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Abstract
The 6-hydroxylation of tryptamine and its various derivatives is a recently discovered enzymatic reaction. Depending upon the structure of the substrate, this process plays a more or less important role in the metabolism of indole derivatives in the intact The most intriguing aspect of this reaction is the greater central-nervous-system effect of the 6-hydroxy metabolites as compared to the nonhydroxyhted parent compounds. In this presentation we describe some of our joint biochemical-behavioral efforts to learn more about this possibly significant reaction. TABLE 1 lists a variety of simple N-alkylated tryptamine derivatives that have psychotropic activity in man. Available evidence indicates that tryptamine alone (that is, not in combination with Marsilid or other enzyme inhibitors) does not produce psychological symptoms? It is interesting, therefore, that several alkyl derivatives of tryptamine can be classed as hallucinogenic. As reported by Szara in Milan in 1957, administration of diethyltryptamine (DET) and dimethyltryptamine (DNIT) leads to rapidly developing sympathomimetic effects, as well as to perceptual, emotional, and thinking disturbances similar to those that result after administration of LSD-25 or me~caline.~ However, these psychological effects persist for only 1 hour in the case of DMT and for about 2.5 hours in the case of DET; in contrast LSD and mescaline have a much longer (6or 8-hour) duration. The dipropyl and diallyl derivatives have similar hallucinogenic activity in man, as we found recently. The psychotropic activity of a-methyltryptamine has been reported by Murphree et aL6 Because all of the derivatives listed in TABLE 1 are 6-hydroxylated in the body, we studied this metabolic reaction in detail, first in animals and then in humans. The 6-hydroxylation reaction takes place in the microsomes of the liver and requires TPNH and On. The 6-hydroxy metabolite is excreted in the urine partly free, partly conjugated to glucuronic acid.' If we incubate the urine with bacterial P-glucuronidase the liberated 6-hydroxy derivative, together with the free form, can be extracted into organic solvents a t alkaline pHs. Since we did most of the animal and human studies with DET, we now describe the quantitative determination of its major metabolite, 6-HDET. FIGURE 1 shows that 6-HDET is stable between pHs of 3 and 8.5, so we developed a procedure for the extraction of 6-HDET within this pH range. An aliquot (15 ml.) of the urine sample, containing 5 to 500 pg of 6-HDET (free and glucuronide), is incubated with approximately 100 mg. of bacterial P-glucuronidase* in the presence of 3 ml. phosphate buffer (PH 7.0) and 0.2 ml. of chloroform at 37" C. in a stoppered flask and subjected to shaking for 2 hours. Five milliliters of the incubated sample is shaken with 15 ml. of n-butanol after * From the Sigma Chemical Co., St. Louis, Mo.
The 6-hydroxylation of tryptamine derivatives in the liver produces psychoactive metabolites with varying central-nervous-system effects, potentially playing a significant role in the metabolism of indole derivatives in the body.
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