A-Hydroxytryptophan

A plausible hypothesis at this stage (about 1943) was that a sequence occurred tryptophan —> an intermediate kynurenine kynurenic acid. It was thought that the intermediate between tryptophan and kynurenine might be the so-called a-hydroxytryptophan (for structure see p. 83), which had been obtained (917) on hydrolysis of phalloidine, a toxic peptide from the fungus Amanita pkalloides (567) such a pathway received... 

The nature of the intermediate A aroused widespread interest. The work already described suggested that it was a-hydroxytryptophan (more correctly described as oxindolylalanine, 157), which chemically is a plausible precursor of formylkynurenine (c/. review, 170). 

Tryptophan pyrrolase appears to be absolutely specific for both substrates. Until this time, no substrates have been found to substitute for L-tryptophan D-tryptophan, tryptamine, indole-3-propionate, acetyl tryptophan, 5- and 7-hydroxytryptophan, a-methyl tryptophan, a-hydroxytryptophan, and 2,3-dihydroxytryptophan are all inert with... 

As a result, we could open the door to a new frontier in indole chemistry. Various 1-hydroxyindoles (4a), l-hydroxytryptophans(la), 1-hydroxytryptamines (lb), and their derivatives have been given birth for the first time. As predicted, 1-hydroxytryptophan and 1-hydroxytryptamine derivatives are found to undergo previously unknown nucleophilic substitution reactions. In addition, we have been uncovering many interesting reactivities characteristic of 1-hydroxyindole structures. From the synthetic point of view, useful building blocks for indole alkaloids, hither to inaccessible by the well-known electrophilic reactions in indole chemistry, have now become readily available. Many biologically interesting compounds have been prepared as well. 

Hydroxyindoles carrying a side chain containing a free NH2, OH, or COOH functional group are unstable. Therefore, 1-hydroxytryptophan, -tryptamine, and -indole-3-acetic acid have not been prepared yet. 

Regioselective nucleophilic substitution at the 5 position is proved to occur when 1-hydroxytryptophan and -tryptamine derivatives are treated with 85% HCOOH (99H1157). Truly amazing is the fact that only substrates carrying a C—C—N structure in the side chain at the 3 position can undergo this regioselective substitution. 

With 1-hydroxytryptophan derivatives, similar substituent effects are observed (99H2815). In order to realize better yields of 5-substituted tryptophans, car-boxy and amino groups are transformed to ester and/or amide groups, choosing the 1-methoxy moiety as a leaving group. As a result, ( )-Ab-acetyl-5-chlorotryptophan methyl ester (219, 52%) is obtained together with 220 (7%) from ( )-218 by the reaction with aqueous HCl (Scheme 32). ( )-5-Bromo-Ab-methoxycarbonyltryptophan methylamide (222, 50%) becomes readily available... 

No 1 -hydroxytryptamine or -tryptophan alkaloid that lacks a stabilizing group on the indole nucleus has been reported yet. However, isolation of37,38a, 38b, HUN-7293 (293) (96MI69), and apicidin (301) (96TL8077) offers indirect evidence for the existence of 1-hydroxytryptamines and/or 1-hydroxytryptophans in living organisms. We believe their isolation will be reported in the near future. 

Labetalol HCI 4-Benzyloxyaniline HCI Hydroxytryptophan N-BenzyloxycarbonyI-L-aspartic acid-a-nitrophenyl,/3-benzyl diester Aspartame... 

The product of the hydroxylation of tryptophan, 5-hydroxytryptophan, is rapidly decarboxylated to 5-HT by a specific decarboxylase enzyme. This is generally thought to be a soluble enzyme which suggests that 5-HT is synthesised in the cytoplasm, before it is taken up into the storage vesicles. If this is the case, then considerable losses might be incurred from its metabolism by monoamine oxidase before it reaches the storage vesicles. Indeed, this could explain why 5-HT turnover seems to greatly exceed its rate of release. 

The high affinity of the decarboxylase enzyme for its substrate (10 pM in the brain) makes it unlikely that this stage could ever become rate-limiting for the pathway as a whole. Nevertheless, the for this enzyme is considerably higher than tissue concentrations of 5-hydroxytryptophan and so, again, supply of this substrate is likely to be a crucial factor. 

Coen, C. W., Coombs, M. C., Wilson, P. M. Clement, E. M. 8r MacKinnon, P. C. (1983). Possible resolution of a paradox concerning the use of p-chlorophenylalanine and 5-hydroxytryptophan evidence for a mode of action involving adrenaline in manipulating the surge of luteinizing hormone in rats. Neuroscience 8, 583-91. 

Serotonergic neurons contain the enzyme L-tryptophan-5-monooxygenase (EC 1.14.16.4), more commonly termed tryptophan hydroxylase, which converts tryptophan to 5-hydroxytryptophan (5-HTP) (Fig. 13-5). Tryptophan hydroxylase contains 444 amino acids, corresponding to a molecular weight of about 51 Da. This enzyme is synthesized in serotonergic cell bodies of the raphe nuclei and is found only in cells that synthesize 5-HT. Therefore its distribution in brain is similar to that of 5-HT itself. The Km of tryptophan hydroxylase for tryptophan is approximately 30-60 pmol/1, a concentration comparable to that of tryptophan in brain. If the concentration of tryptophan in serotonergic neurons is assumed to be comparable to that in whole brain, the enzyme would not be saturated with substrate, and the formation of 5-HT in brain would be expected to rise as the brain concentration of tryptophan increases. This has been found to occur in response to raising the dietary intake of tryptophan specifically. 

The acute and chronic effects of Li+ in patients are quite different (reviewed by Goodnick [146]). Initially, Li+ treatment causes an increase in the level of 5-HT and decrease in 5-HT uptake in platelets, with an increase in the level of 5-HIAA in the CSF. The neuroendocrine responses to the 5-HT precursors, tryptophan and 5-hydroxytryptophan [160], and to flenfluramine [161], a 5-HT releaser, are enhanced by Li+. Thus the combined effect of acute Li+ treatment is to increase the efficiency of synaptic 5-HT. However, chronic Li+administration results in almost the opposite effect, resulting in responses close to the levels... 

Nozaki, M., Bell, J. A., Vaupel, D. B., and Martin, W. R. (1977) Responses of the flexor reflex to LSD, tryptamine, 5-hydroxytryptophan, methoxamine, and d-amphetamine in acute and chronic spinal rats. Psychopharmacology, 55 13-16. 

The 4-phenyl and 4-phenyl-2-oxo analogues of (6, n = 3 R1 = R2 = Me) have been reported to exhibit sedative properties [13]. Several carboxamides (7) with a 4-phenyl group have been claimed to be useful as tranquillizers [ 14]. A variety of central effects of the 1-substituted 5-phenyl derivatives (8) has been studied [10]. The 2-(substituted aminomethyl)tetrahydro-l-benzazepine and octahydropyrazino[ l,2-c]-l-benzazepine derivatives have no pharmacological activity on the CNS [15]. 1-Substituted tetrahydro-l-benzazepines having an aminoalkyl group at position 3 are claimed to potentiate the activity of 5-hydroxytryptophan [16]. 

Several amino acids are broken down by de-carbo qflation. This reaction gives rise to what are known as biogenic amines, which have various functions. Some of them are components of biomolecules, such as ethanolamine in phospholipids (see p. 50). Cysteamine and T-alanine are components of coenzyme A (see p.l2) and of pantetheine (see pp. 108, 168). Other amines function as signaling substances. An important neurotransmitter derived from glutamate is y-aminobutyrate (GABA, see p.356). The transmitter dopamine is also a precursor for the catecholamines epinephrine and norepinephrine (see p.352). The biogenic amine serotonin, a substance that has many effects, is synthesized from tryptophan via the intermediate 5-hydroxytryptophan. 

Sallinen J, Haapalinna A, Viitamaa T, Kobilka BK, Scheinin M (1998) Adrenergic Ojc-receptors modulate the acoustic startle reflex, prepulse inhibition, and aggression in mice. J. Neuroscience 18 3035-3042 Sallinen J, Haapalinna A, Viitamaa T, Kobilka BK, Scheinin M (1998) D-amphetamine and L-5-hydroxytryptophan-induced behaviours in mice with genetically-altered expression of the a2c-adrenergic receptor subtype. Neuroscience 86 959-965... 

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