6- Hydroxytryptophan

Therapeutic Function CNS stimulant Chemical Name 5-hydroxytryptophan Common Name — 

4-Benzyloxyaniline HCI Hydrochloric acid Sodium hydroxide Diethylacetylamino malonate 

Sodium nitrite Stannous chloride Acrolein Hydrogen 

Preparation of 4-Benzy/oxypheny/hydrazine 200 grams 4-benzyloxyaniline hydrochloride was suspended in a mixture of 264 ml concentrated hydrochloric acid, 528 ml water and 732 grams crushed ice. A solution of 62.4 grams sodium nitrite in 136 ml water was added below the surface of the stirred suspension at -10 2°C during 10 minutes. After stirring for 1 hour at 0°C, the suspension was treated with acid-washed charcoal and filtered. 

The filtrate was cooled and maintained at -8°C while a solution of 500 grams of stannous chloride in 760 ml concentrated hydrochloric acid was added with stirring. The mixture was stirred for 2 hours at -S C and the 4-benzyloxyphenylhydrazine hydrochloride which Separated was filtered off and washed with water. The product was crystallized by adding 800 ml hot water to a 3 liter solution in ethanol and had a MP of 185° to 189°C (yield 168.5 grams, 79%). 

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Therapautic Function Antidepressant, antiepileptic Chemicel Name 5-Hydroxytryptophan Common Name 5-Hydroxytryptophan Structural Formula ... 

Hydroxytryptamine 380 5-Hydroxytryptophan 240,241 Hydroxytyramine 392 Hyodesoxycholic acid 334 Hyperici, Extract. 279 Hypericin 148, 279, 280 Hyperoside 149,279,323 -, -quercetin 280... 

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. 

Bogdanski, D.F. Weissbach, H. and Udenfriend, S. The distribution of serotonin, 5-hydroxytryptophan decarboxylase, and monoamine oxidase in brain. J Neurochem 1 272-278, 1957. 

Rahman, M. K Nagatsu, T., and Kato, T. (1981). Aromatic L-amino acid decarboxylase activity in central and peripheral tissues and serum of rats with L-DOPA and L-5-hydroxytryptophan as substrates. Biochem. Pharmacol. 30 645-649. 

The precursor for the synthesis of 5-HT is the amino acid L-tryptophan, which is obtained from dietary protein (Fig. 2.2A). L-tryptophan is converted to 5-hydroxytryptophan (5-HTP) in serotonin neurons by the enzyme tryptophan... 

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. 

Figure 9 Chromatogram of 5-hydroxyindoles derivatized with 6-AMP. Peaks (2.5 pmol each on column) 1 = 5-hydroxytryptophan 2 = serotonin 3 = 5-hydroxyindole-3-acetic acid. (From Ref. 50.)...

Serotonin is synthesized from tryptophan in two steps. Tryptophan is hydroxylated by tryptophan hydroxylase, and 5-hydroxytryptophan is decarboxylated to give serotonin. Most serotonin in the body is found in the enterochromaffin cells of the intestinal tract and the pineal gland. Platelets take up and store serotonin but do not synthesize it. 

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... 

Nakamura, M., Fukushima, H., and Kitagawa, S. (1976) Effect of amitriptyline and isocarboxazid on 5-hydroxytryptophan induced head twitches in mice. Psychopharmacology, 48 101-104. 

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. 

Trulson, M. E., and Jacobs, B. L. (1976) Dose-response relationships between systemically administered 1-tryptophan or 1-5-hydroxytryptophan and raphe unit activity in the rat. Neuropharmacology, 15 339-344. 

Stewart, R. M., Growdon, J. H., Cancian, D., and Baldessarini, R. J. (1976) Myoclonus after 5-hydroxytryptophan in rats with lesions of indoleamine neurons in the central nervous system. Neurology, 26 690-692. 

Wyatt, R. J., Vaughan, T., Galanter, M., Green, R., and Kaplan, J. (1972) Behavioral changes of chronic schizophrenic patients given L-5-hydroxytryptophan. Science, 177 1124-1126. 

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]. 

Serotonin is an indolamine neurotransmitter, derived from the amino acid L-tryptophan. Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase. 5-HTP is converted to 5-hydroxytryptamine (serotonin, 5-HT) by aromatic amino acid decarboxylase. In the pineal gland, 5-HT may be further converted to /V-acetyl serotonin by 5-HT /V-acetyltransferase and then to melatonin by 5-hyroxyindole-O-methyltransferase. 5-HT is catabolized by monoamine oxidase, and the primary end metabolite is 5-hydroxyindoleacetic acid (5-HIAA). 

Following the synthesis of 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase, the enzyme aromatic amino acid decarboxylase (also known as 5-HTP or dopa decarboxylase) then decarboxylates the amino acid to 5-HT. L-Aromatic amino acid decarboxylase is approximately 60% bound in the nerve terminal and requires pyridoxal phosphate as an essential enzyme. 

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