5- Hydroxytryptamine derivatives

G. Fillion, B. Dupraz, N. Prudhomme, T. Huynh-Dinh, Blood-Brain Penetration of 5-Hydroxytryptamine Derivatives , Bioorg. Med. Chem. Lett. 1994, 4, 1485-1490. 

Leptodactylus pentadactylus and L. ocellatus native to South and Central America, contain considerable amounts of 5-hydroxytryptamine derivatives, like N-methylserotonine, bufotenin and bufotenidin as well as leptodactylin and candicin (ref. 4). Of a new type are substances like histamin, methyl-, and acetyl-histamins, and spinaceamin. Spinaceamin can be synthesized in vitro by a biomimetic reaction of histamin and formaldehyde in aqueous solution at pH 6.8, and room temperature (ref. 5). 

The binding of 7-substituted-5-hydroxytryptamine derivatives to an LSD receptor site correlates with the frontier electron density (fj ) and charge of the ring nitrogen (position 1), modified by... 

Salmoun, M., Devijver, C., Daloze, D., Braekman, J.C., and Van Soest, R.W.M. (2002) 5-Hydroxytryptamine-derived alkaloids from two marine sponges of the genus Hyrtios.J. Nat. Prod., 65, 1173-1176. 

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. 

The unprecedented nucleophihc substitution reaction on the indole nitrogen N(l) was discovered when 1-hydroxyindoles were reacted with good nucleophiles in 85% HCOOH [1-7]. Since then, this type of reaction has been widely observed among the reactions of 1-hydroxytryptamine derivatives and many examples have been accumulated. 

In our project to develop a drug for osteoporosis, we have created 1-hydroxytryptophan ((d/)-41) and 1-hydroxytryptamine derivatives (52, 185, and 30). Among them, (dO-41 and 52 have the same trend not only to stimulate osteoblasts, but also to suppress osteoclast activity in the cultured scales of goldfish [48,49], On the other hand, compounds (185 and 30 suppress both osteoblasts and osteoclasts. During the study, we have succeeded in creating potent and promising compoimds for osteoporosis [50,51],... 

The surface of the green coffee contains a cuticular wax layer (0.2—0.3% db) for both varieties. The wax contains insoluble hydroxytryptamides derived from 5-hydroxytryptamine [61 7-2] and saturated C18—C22 fatty acids. 

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... 

Chemistry and biological properties of polyfunctional indole-3-carbinol derivatives [l-(indol-3-yl)glycerols and related compounds, (3-hydroxytryptamines, and ascorbigens] 95F369. 

Attempts to extend the reaetion to the syntheses of 5-ehloro and 5-bromo derivatives have led us to diseover that treating 1-hydroxytryptamines simply with aqueous hydrogen halides at room temperature is suffieient to meet our end (99H2815). 

Very little is known about the occurrence of 1-hydroxytryptamine and/or 1-hydroxytryptophan derivatives in living organisms. Many 1-methoxyindole derivatives have been isolated as natural products (87MI629, 88BCJ285, 92H1877, 93MI22) for the simple reason that they are stable under isolating processes. 

Serotonin or 5-hydroxytryptamine is an important biogenic amine, which is synthesized via 5-hydroxy-tryptophan from the amino acid tryptophan. The highest concentration of serotonin occurs in the wall of the intestine. About 90% of the total amount is present in enterochromaffrn cells, which are derived from the neural crest, similarly to those of the adrenal medulla. 

Important products derived from amino acids include heme, purines, pyrimidines, hormones, neurotransmitters, and biologically active peptides. In addition, many proteins contain amino acids that have been modified for a specific function such as binding calcium or as intermediates that serve to stabilize proteins—generally structural proteins—by subsequent covalent cross-hnk-ing. The amino acid residues in those proteins serve as precursors for these modified residues. Small peptides or peptide-like molecules not synthesized on ribosomes fulfill specific functions in cells. Histamine plays a central role in many allergic reactions. Neurotransmitters derived from amino acids include y-aminobutyrate, 5-hydroxytryptamine (serotonin), dopamine, norepinephrine, and epinephrine. Many drugs used to treat neurologic and psychiatric conditions affect the metabolism of these neurotransmitters. 

Some derivatives of adamantane with antagonist or agonist effects have also been synthesized. For instance, monocationic and dicationic adamantane derivatives block the a-amino-3-hydroxy-5-methylisoxazole -propionic acid (AMPA) receptors, A-methyl-o-aspartate (NMDA) receptors [134—136] and 5-hydroxytryptamine (5-HT3) receptors [137]. 

Inflammation is a non-specific reaction which can be induced by a variety of agents apart fiom microorganisms. Lymphokines and derivatives of arachidonic acid, including prostaglandins, leukotrienes and thromboxanes are probable mediators of the inflammatory response. The release of vasoactive amines such as histamine and serotonin (5-hydroxytryptamine) firm activated or damaged cells also contribute to inflammation. 

Bradley, P. B., and Briggs, 1.(1974) Further studies on the mode of action of psychotomimetic drugs Antagonism of the excitatory action of 5-hydroxytryptamine by methylated derivatives of tryptamine. Br. J. Pharmacol., 50 345-354. 

More than twenty indole derivatives have been identified from bufonid skin extracts. The indolylalkylamines bufotenidine, bufotenine, de-hydrobufotenine, bufo-tionine and serotonin (5-hydroxytryptamine) (Fig. 39.2b) have been identified in skin secretions of Bufo marinus, while the latter four have been detected in parotoid gland secretions (Erspamer 1994 Maciel, Schwartz, Pires Jr, Sebben, Castro, Sousa, Fontes and Schwartz 2003). The concentration of serotonin in the dried secretion of B. marinus was found to equate to approximately 0.1% of the total composition and primarily acts as a vasoconstrictor (Gregerman 1952 Toledo and Jared 1995). 

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). 

Some rather important indole derivatives influence our everyday lives. One of the most common ones is tryptophan, an indole-containing amino acid found in proteins (see Section 13.1). Only three of the protein amino acids are aromatic, the other two, phenylalanine and tyrosine being simple benzene systems (see Section 13.1). None of these aromatic amino acids is synthesized by animals and they must be obtained in the diet. Despite this, tryptophan is surprisingly central to animal metabolism. It is modified in the body by decarboxylation (see Box 15.3) and then hydroxylation to 5-hydroxytryptamine (5-HT, serotonin), which acts as a neurotransmitter in the central nervous system. 

Also known to be hallucinogenic are the indole derivatives psilocin and psilocybin found in the so-called magic mushrooms, Psilocybe species. Ingestion of these small fungi causes visual hallucinations with rapidly changing shapes and colours. Psilocybin is the phosphate of psilocin although based on 4-hydroxytryptamine, they also act on 5-HT receptors. 

From L-tryptophan, the serotonin synthesis pathway also begins. Serotonin is 5-hydroxytryptamine. It is derived from L-tryptophan, which at first is simply hydroxylated to 5-hydroxy-L-tryptophan, and subsequently to the serotonin (Figure 39). Structurally, serotonin is also a 5-HT monoamine neurotransmitter. 

To measure serotonin (5-hydroxytryptamine), by the internal standard method, a 1 ml aliquot of the unknown solution is added to 1 ml of a solution containing 30 ng of N-methyl-serotonin. This mixture is then treated to remove all other compounds which could interfere with the experiment. The operation performed was an extraction in the solid phase to isolate the serotonin and its methyl derivative, diluted in a suitable medium. 

Not much is known of its chemistry. Positive tests for alkaloids have been obtained in several species S-hydroxytryptamine has been identified in Urlica the substance responsible for the burning sensation from the leaves of Laporlea is a complex octapeptidc piperidine derivatives are found in the family as well. 

Tryptamine and its Al-methyl and A/Al-dimethyl derivatives (Figure 6.70) are widely distributed in plants, as are simple hydroxylated derivatives such as 5-hydroxytryptamine (serotonin). These are formed (Figure 6.70) by a series of decarboxylation, methylation, and hydroxylation reactions, though the sequences of these reactions are found to vary according to final product and/or... 

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