5-Hydroxytryptamine formation

It has been suggested that the blue-green fluoreseenee produeed when 5-hydroxytryptamine is treated with ninhydrin is due to the formation of jS-earboline derivatives and that a brilliant orange-red... 

The reaction of Ab-acetyl-1 -hydroxytryptamine (39) with mesyl chloride (MsCl) in THF in the presence of EtsN provides 1-acetyl-1,2,3,8-tetrahydropyrrolo[2,3-(j] indole (49a, 35%) (70JA343), Ab-acetyl-6-mesyloxytryptamine (50a, 4%), Ab-acetyl-2,3-dihydro-2-oxotryptamine (51a, 5%), l-acetyl-3a-(4-chlorobutoxy)-l,2,3,3a,8,8a-hexahydropyrrolo[2,3-(j]indole (52a, 7%), and Ab-acetyltryptamine (53a, 2%) as shown in Scheme 6 (2000H483). In the same reaction with MsCl, l-hydroxy-Ab-methoxycarbonyltryptamine (34) produces 50b (7%), 51b (34%), and 52b (9%), while the formation of 49b is not observed at all. In the case of Ab-trifluoroacetyl-l-hydroxytryptamine (48), 49c (45%), 50c (8%), 51c (4%), and 52c (6%) are produced. These data suggest that the yield of 49 increases, whereas the yield of 51 decreases in the order of electron-withdrawing ability of Ab substituents (COOMe < COMe < COCF3). Stability of 49 seems to govern the quantity of 51, which is probably formed by hydrolysis of 49. 

COMMENT We feel that it is due to the formation of 5,6-DHT in the eortex. These cells are indeed innervated by serotonin cells and, as a matter of fact, we have an experiment that is being published in Brain Research where we show that if we injeet 5,6-DHT into the ventricles, we ean produce exactly the same type of degeneration in the pyramidal cells, due to the formation of the 5,6 from the 5-hydroxytryptamine. We are exploring the possibility of it being another catecholamine in addition to dopamine, so I think both of those may be helpful in answering your question. 

Mansour, T. E., Sutherland, E. W., Rail, T. W., and Bueding, E. (1960) The effect of serotonin (5-hydroxytryptamine) on the formation of adenosine 3, 5 -phosphate by tissue particles from the liver fluke, Fasciola hepatica. J. Biol. Chem., 235 466-470. 

The pathways for synthesis of the monoamine neurotransmitters are not, at least in some neurones, saturated with precursor amino acids (tyrosine for formation of noradrenaline plus dopamine tryptophan for formation of 5-hydroxytryptamine (serotonin)). Marked increases in the blood level of these amino acids can increase their concentrations in neurones which can influence the concentration of the respective neurotransmitters in some neurones in the brain. This may result in changes in behaviour. 

Figure 13.28 A possible mechanism by which increased levels of tryptophan and/or tyrosine can occur in neurones and lead to fatigue. The mechanism proposes that physical activity increases the entry of tryptophan or tyrosine into the neurones which increases the concentration of the neurotransmitters, 5-hydroxy-tryptamine or dopamine, respectively. The neurotransmitters are present in vesicles in the presynaptic terminal (Chapter 14). (The pathways for the formation of 5-hydroxytryptamine and dopamine are described in Chapter 14.) This enhances the amount release into the synapses which decreases the excitation of 5-hydroxytryptamine or dopamine neurones in the motor control pathway. It is assumed that they are inhibitory neurotransmitters, they will reduce electrical activity in the motor control pathway and hence nervous stimulation of muscle fibres. This results in fatigue. Mechanisms by which physical activity might result in increased entry of these amino acids into the brain are presented in Appendix 13.5.

Neuronal systems that contain one of the monoamines—norepinephrine, dopamine, or 5-hydroxytryptamine (serotonin)— provide examples in this category. Certain other pathways emanating from the reticular formation and possibly some peptide-containing pathways also fall into this category. These systems differ in fundamental ways from the hierarchical systems, and the noradrenergic systems serve to illustrate the differences. 

In an effort to investigate antioxidant constituents with antiproliferative effects in rat vascular smooth muscle cells (VSMC), broussoflavan A (36) [49], broussoflavonols F (45) [50] and G (46) [51], and broussoaurone A (48) [49] were found to inhibit the Fe2+-induced thiobarbituric acid-reactive substance formation in rat brain homogenate. Furthermore, broussoflavonols F (45) and G (46) inhibited fetal calf serum-, 5-hydroxytryptamine-, or ADP-induced [3H]thymidine incorporation into rat VSMC [45]. Antioxidant activities and inhibitory effects on proliferation of rat VSMC with potent antiplatelet activities of 45 and 46 may be useful for vascular diseases and atherosclerosis [43,45]. 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

Tohda M, Tohda C, Oda H, Nomura Y. Possible involvement of botulinum ADP-ribosyltransferase sensitive low molecular G protein on 5-hydroxytryptamine (5-HT)-induced inositol phosphates formation in 5-HT2c cDNA transfected cells. Neurosci Lett 1995 190 33-36. 

Ford AP, Baxter GS, Eglen RM, Clarke DE. 5-Hydroxytryptamine stimulates cyclic AMP formation in the tunica muscularis mucosae of the rat oesophagus via 5-HT4 receptors. Eur J Pharmacol 1992 211 117-120. 

Figure 9.125 Relationship between amine concentration and oxidation product formation at a fixed level of ceruloplasmin. Oxidation of adrenaline ( ) was monitored at 300 nm oxidation of 5-hydroxytryptamine (O) was monitored at 315 nm. (From Richards, 1983.)...

There is a great deal of evidence that deficiency of serotonin (5-hydroxytryptamine) is a factor in depressive illness, and many antidepressant drugs act to decrease its catabolism or enhance its interaction with receptors. A key enzyme involved in the synthesis of serotonin (and the catecholamines) is aromatic amino acid decarboxylase, which is pyridoxal phosphate-dependent. Therefore, it has been suggested that vitamin Be deficiency may result in reduced formation of the neurotransmitters and thus be a factor in the etiology of depression. Conversely, it has been suggested that supplements of vitamin Be may increase aromatic amino acid decarboxylase activity, and increase amine synthesis and have a mood-elevating or antidepressant effect. There is little evidence that vitamin Be deficiency affects the activity of aromatic amino acid decarboxylase. In patients with kidney failure, undergoing renal dialysis, the brain concentration of pyridoxal phosphate falls to about 50% of normal, with no effect on serotonin, catecholamines, or their metabolites (Perry etal., 1985). 

Central effects on blood pressure regulation as a result of decreased synthesis of brain GABA and serotonin (5-hydroxytryptamine). Glutamate decarboxylase activity in the nervous system is especially sensitive to vitamin Bg depletion, possibly as a result of mechanism-dependent inactivation by transamination. Although there is no evidence that aromatic amino acid decarboxylase activity is reduced in vitamin Bg deficiency, there is reduced formation of serotonin in the central nervous system. 

Fluid and electrolyte loss in cholera patients is closely related to elevated concentrations of cAMP, which can stimulate chloride secretion in intestinal epithelial cells (Field, 1971 Moss and Vaughan, 1988a). There is also evidence for the importance of other substances, such as prostaglandin E2 (PGE2) and 5-hydroxytryptamine (5-HT), in CT-induced secretion (Kaper et al., 1995). Nilsson et al. (1983) reported that 5-HT was released from enterochromaffin cells in the cat small intestine upon CT treatment. 5-HT could then stimulate PGE2 synthesis (Beubler etai, 1989) and activate the enteric nervous system (Ekiund et al., 1984). Cholera toxin also caused release of PGE2 into the lumen of intestinal loops in vitro (Peterson and Ochoa, 1989), via an effect on arachidonic acid formation (Peterson et al., 1990 Reit-meyer and Peterson, 1990). The contribution of these, and perhaps other, CT effects to the pathogenesis of cholera remains to be elucidated (Peterson etai, 1994). 

Pyridoxal phosphate is the coenzyme in a large number of amino acid reactions. At this point it is convenient to consider together 1,he mechanism of those pyridoxal-dependent reactions concerned with aromatic amino acids. The reactions concerned are (1) keto acid formation (e.g., from kynurenine, above), 2) decarboxylation (e.g., of 5-hydroxytrypto-phan to 5-hydroxytryptamine, p. 106), (3) scission of the side claain (e.g., 3-tyrosinase, p. 78 tryptophanase, p. 110 and kynureninase, above), and 4) synthesis (e.g., of tryptophan from indole and serine, p. 40). Many workers have considered the mechanism of one or more of these reactions (e.g., 24, 216, 361, 595), but a unified theory is primarily due to Snell and his colleagues (summarized in 593). Snell s experiments have been carried out largely in vitro, and it should be emphasized that in vivo it is the enzyme protein which probably directs the electromeric changes. 

Dopa is decarboxylated to 2-(3,4-dihydroxyphenyl) ethylamine (dopamine) by aromatic L-amino acid decarboxylase, a nonspecific cytosolic pyridoxal phosphate-dependent enzyme also involved in formation of other amines (e.g., 5-hydroxytryptamine). 

Pellagra-like symptoms can occur in Hartnup s disease and carcinoid syndrome. Hartnup s disease is an inherited disorder of amino acid transport (Chapter 17) in which niacin deficiency presumably develops because niacin intake is inadequate to supply metabolic needs when combined with the decreased absorption of dietary tryptophan. In carcinoid syndrome, up to 60% of available dietary tryptophan is diverted to formation of 5-hydroxytryptamine (serotonin) by what is normally a minor pathway. 

Tryptophan appears to be converted to a larger number of metabolites than any of the other amino acids. The degradation of tryptophan in animals occurs mainly in two pathways, I and II (Figure 4.1). The first major pathway (I), initiated by the action of tryptophan dioxygenase, involves oxidation of tryptophan to N - fc > r my I ky n urenine and the formation of a series of intermediates and byproducts, most of which appear in varying amounts in the urine, the sum of which accounts for the total metabolism of tryptophan, approximately. The second pathway (II) involves hydroxylation of tryptophan to 5-hydroxytryptophan and decarboxylation of this compound to 5-hydroxytryptamine (serotonin), a potent vasoconstrictor found particularly in the brain, intestinal tissues, blood platelets, and mast cells. A small percentage (3%) of dietary tryptophan is metabolized via the pathway (III) to indoleacetic acid. Other minor pathways also exist in animal tissues. 

Viani and Horman (1976) found indole on roasting serotonin (hydroxytryptamine, 2-aminoethyI-I//-indol-5-ol), present as an amide in the waxes surrounding the coffee bean and which behaves like the related tryptophan. A pathway showing its formation in the thermal degradation of phenylalanine at 300 °C has been published by Kato et al. (1971). 

Indomethacin is a potent anti-inflammatory and anti-pyretic compound. Given orally, it inhibits the formation of the cotton-pellet granuloma in the rat, being about 85 times more potent than phenylbutazone, and equally active in both intact and adrenalectomized rats. It inhibits oedema of the rat-foot, produced by either carrageenan or mustard, but does not inhibit that produced by egg-white, formalin, yeast or 5-hydroxytryptamine. As an antipyretic, it is 10-20 times more powerful than phenylbutazone. Indomethacin is well absorbed in all species, but there is considerable variation in its distribution and metabolism. Man tolerates the drug better than do other species, and is less liable to the gastro-intestinal irritation encountered in experimental animals . ... 

The enzymes involved in the formation of the catecholamines are of low specificity. DOPA decarboxylase, or an enzyme closely akin to it, is concerned in the formation of 5-hydroxytryptamine > dopamine-/9-oxidase has been shown to be capable of hydroxylating the jd-carbon atom of a number of tyramine derivatives - and phenylethanolamine A-methyltransferase is equally unselective in its A-methylation of noradrenaline derivatives . This lack of specificity suggests the possibility that alternative pathways for the formation of noradrenaline and adrenaline might exist in vivo. Some of the putative intermediaries in these other pathways have been shown to occur naturally and one of them, octopamine (/) is found in the brain . 

The other physiologically important monoamine is 5-hydroxytryptamine (serotonin or 5-HT). It is formed from tryptophan via 5-hydroxytryptophan (5-HTP) Figure 5.2). The nature and properties of tryptophan-5-hydroxy-lase is still obscure, though the hydroxylation of tryptophan in vivo has been demonstrated. There is no clear evidence that this conversion occurs in brain tissue. The decarboxylation of 5-HTP, however, takes place in brain and the decarboxylating enzyme is found in all cerebral areas which contain 5-hydroxytryptamine. 5-HTP decarboxylase is closely related to, if not identical with, DOPA decarboxylase - and agents which inhibit dopan ine formation similarly inhibit the production of 5-hydroxytryptamine. There... 

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