5-Hydroxyindole-3-acetaldehyde

After its reuptake into nerve cells, serotonin is degraded in a two-step pathway (Figure 15.11). In the first reaction, serotonin is oxidized by MAO. The product, 5-hydroxyindole-3-acetaldehyde, is then further oxidized by aldehyde dehydrogenase to form 5-hydroxyindole-3-acetate. 

Serotonin, or 5-HT, is biosynthesized (3) from its dietary precursor L-tryptophan (Fig. 14.1). Serotonergic neurons contain tryptophan hydroxylase (L-tryptophan-5-monooxygenase) that converts tryptophan to 5-hydroxytryptophan (5-HTP) in what is the rate-limiting step in 5-HT biosynthesis and aromatic L-amino acid decarboxylase (previously called 5-HTP decarboxylase) that decarboxylates 5-HTP to 5-HT. This latter enzyme also is responsible for the conversion of L-DOPA to dopamine (see Chapter 12). The major route of metabolism for 5-HT is oxidative deamination by monoamine oxidase (MAO-A) to the unstable 5-hydroxyindole-3-acetaldehyde, which is either reduced to 5-hydroxytryptophol ( 15%) or oxidized to 5-hydroxyindole-3-acetic acid ( -85%). In the pineal gland, 5-HT is acetylated by 5-HT N-acetyltransferase to N-acetylserotonin, which undergoes O-methylation by 5-hydroxyindole-O-methyltransferase to melatonin. 

Using the partially purified soluble MAO which had been separated from aldehyde dehydrogenase, it was possible to obtain appreciable quantities of the intermediate, 5-hydroxyindole-3-acetaldehyde, and to determine some of its properties. Contrary to expectations this aldehyde was found to be relatively stable when kept in dilute solution. This same enzyme preparation was used to prepare the corresponding aldehyde from norepinephrine, i.e., 3,4-dihydroxyphenylglycolic aldehyde (keeper et al., 1958). It is of interest that this aldehyde was also found to be surprisingly stable in dilute aqueous solution. 

The blood-brain barrier foils most efforts to use the blood to measure the brain s chemistry, but researchers can get aroimd this obstacle by sampling cerebrospinal fluid (CSF). CSF is the fluid that circulates in the meninges of the brain and spinal cord and keeps the delicate tissues from getting rattled around and damaged in their hard, bony container. The brain makes CSF from blood, and certain metabolites get mixed in. One of these metabolites is 5-hydroxyindole acetaldehyde (5-FIIAA), a major metabolite of serotonin. Researchers who carefully puncture the meninges and extract a sample are rewarded with information concerning serotonin levels in the person s brain, as described below. 

The hydroxylation of tryptophan produces 5-hydroxytryptophan, which can then be decarboxylated, catalyzed by tryptophan decarboxylase, a PALP-requiring enzyme, to 5-hydroxy tryptamine, also known as serotonin. Serotonin is an important compound in normal brain function and tranquility. Therefore, any disturbance of tryptophan metabolism via this pathway can lead to mental disturbances. Serotonin can be destroyed by the enzyme monoamine oxidase (a flavo protein), which catalyzes the formation of ammonia and 5-hydroxyindole acetaldehyde in an irreversible reaction. The aldehyde is rapidly oxidized enzymatically, utilizing NAD+ to form 5-hydroxy indoleacetate, which is then usually excreted. The formation and turnover of serotonin can be estimated by 5-hydroxy indoleacetate output in the urine. 

Of much interest is the recent discovery of substances closely related to the harmala alkaloids in animals. One of these is adrenoglomerulotropine, a hormone of the pineal body, the chemical identity of which has been indicated as 2,3,4,9-tetrahydro-6-methoxy-i-methyl-iH-pyrido (3,4,6) indole. This substance is identical to 6-methoxyletrahydroharman which has been shown to be formed in vivo from 5-methoxy tryptamine and acetaldehyde. 6-methoxytetrahydroharman is an isomer of tetrahydro-harmine, one of the alkaloids in Banisteriopsis, and in the African Leptactinia densillora. One more substance, 6-methoxyharmalan, has been shown to derive, at least in vitro, from melatonin, which results from the methylation of acetylserotonin. The enzyme which makes this possible, hydroxyindole O-methyl transferase, has only been found in the pineal body. (Naranjo, in Efron et al. 

In the major catabolic pathway, serotonin is deaminated and oxidized to form 5-hydroxyin-dole-3-acetaldehyde. The latter molecule is then further oxidized to form 5-hydroxyindole-3-acetate. 

Indoles and Carbazoles. - Formation. 2-Arylindoles (132) are formed by intramolecular Wittig reaction of the phosphonium salts (131). The hydroxamic acids PhN(OH)COCH2COR (R = alkyl or aryl) cyclize in boiling toluene to mixtures of indoles (133) and 3-isoxazolones (134). Irradiation of a solution of o-iodoaniline and the potassium enolate of acetone affords 2-methylindole. The enamino-ketone (135) cyclizes photochemically to 1,2-dimethylindole (136) with elimination of acetaldehyde/ The styrene derivative (137), obtained by the action of Meerwein s acetal, Me2NCH(OMe)2, on o-nitrotoluene, yields 1-hydroxyindole on treatment with zinc/ Azidobenzocyclobutanes (138 R = Me, Ph, or CH2Ph) are converted into indoles (133) by the action of concentrated sulphuric acid/ ... 

The VNS reaction of 4-nitroanisole with ethyl chloroacetate followed by the Knoevenagel condensation of the product with acetaldehyde affords a-(2-nitrophenyl)crotonate, which in the presence of f-BuOK in ferf-butanol undergoes cyclization into V-hydroxyindole-3-carboxylate (Scheme 76). Further alkylation of the latter compound with methyl iodide results in Af-methoxyindole. It is worth mentioning that in this reaction a partial loss of the alkene chain does happen to occur [194]. A similar phenomenon has been observed earlier in our laboratory [195]. 

An aromatic nitro group sometimes participates in the formation of indoles, in particular of N-hydroxy derivatives. For example, the reaction of ort/io-nitroaryl substituted acetonitriles 29 with acetaldehyde followed by treatment with K2CO3 afforded N-hydroxyindoles 30, as the major products [38] (Scheme 16). 

The 3-hydroxyindole structure can be found in many natural products, as exemphlied by convolutamydines, madindolines, and CPC-1 93. Hayashi and co-workers reported on an asymmetric catalytic direct aldol reaction of isatin 90 with acetaldehyde in the presence of a proline-derived organocatalyst (Scheme 27.16). In this reaction. 

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