N-Hydroxytryptophan

It has been demonstrated that N-hydroxytryptophan can be converted to /3-carbolines in two ways (Fig. 41). Pictet-Spengler reaction of 1 with acetals provided the N -hydroxytetrahydro-/8-carbolines (2) (287). A modified Bischler-Napieralski reaction of 1 with trimethylorthoformate gave N -0X0-3,4-dihydro-/3-carbolines (3), the nitrone function of which can undergo 1,3-dipolar cycloaddition with alkenes (288) and nitriles (289), providing isoxazolidine (4) and dehydro-1,2,4-oxadiazoline (5), annulated TBCs, respectively. Nitrone 3 also was obtained by oxidation of the N-hydroxy-j8-carboline 2 with 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone (DDQ). N-Oxygenated TBCs showed no affinity for the benzodiazepine and tryptamine receptors (290). Unfortunately, no toxicity data were recorded for these substituted hydroxylamines. 

A nitrone obtained from an N-hydroxytryptophan ester and methyl orthoformate afforded a route to 8-carbolines via nitrone cycloaddition. 

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. 

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

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]. 

Joyce D, Hurwitz HMB Avoidance behaviour in the rat after 5-hydroxytryptophan (5-HTP) administration. Psychopharmacologia 5 424-430, 1964 Joyce EM The neurochemistry of Korsakoff s syndrome, in Cognitive Neurochemistry. Edited by Stahl SM, Iversen SD, Goodman EC. Oxford, England, Oxford Science Publications, 1987, pp 327-345 Judd EK, Chua P, Lynch C, et al Eenfluramine augmentation of clomipramine treatment of obsessive compulsive disorder. Aust N Z J Psychiatry 25 412-414, 1991 Judge R, Steiner M The long-term efficacy and safety of paroxetine in panic disorder. 

Serotonin is synthesized via tryptophan and 5-hydroxytryptophan with decarboxylation of the latter (Fig. 25-12). Within the pineal body of the brain and in the retina, serotonin is acetylated to N-acetylseroto-nin,782/783 which is then O-methylated to melatonin, the pineal hormone (Fig. 25-12). A specific inhibitor of serotonin synthesis is p-chlorophenylalanine, and studies with this and other inhibitors suggest that serotonin is required for sleep.784... 

The stereochemistry of the modified tryptophan amino acids in the previously known konbamide and keramamide A sponge metabolites (/ ) has been determined to be l for both 2-bromo-5 -hydroxytryptophan and 6-chi oro-5 - hydro x v-/V-methyltryptophan, respectively (1066). However, based on synthetic studies, doubt has been raised as to the structure of konbamide (1067). A series of investigations of Okinawan Theonella sp. sponges has uncovered the new halo-genated keramamides, E (1031), H (1032) (1068), L (1033) (1069), M (1034), and N (1035) (1070). 

Fig. 5 Tryptophrin is converted to 5-hydroxytryptophan by tryptophan hydroxylase (1). The production of serotonin in the next step is catalysed by 5-HTP decaiboxylase (a PLP-dependent enzyme). Serotonin is then acetylated to N-acetyl-serotonin by N-acetyltransferase (2). Melatonin is then produced via the action of hydroxyindole-O-methyltransferase (3)...

C11H12N203 L-5-hydroxytryptophan 4350-09-8 25.00 1.2427 2 22048 C11H14CIN02 N-butyl-4-chloro-2-hydroxybenzamide 575-74-6 25.00 1.1763 2... 

Some tryptamine molecules found naturally in the human body include tryptophan, 5-hydroxytryptophan, serotonin, melatonin, and N,N-dimethyltryptamine. 

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. 

Substrate specificity of the purified indoleamine 2,3-dioxygenase from rabbit intestine was examined spectrophotometrically at 24°C. The spectra of the reaction products in either the absence or presence of formamidase were compared with those of authentic compounds. A single enzyme protein catalyzed the oxygenative ring cleavage of d- and L-tryptophan, 5-hydroxy-D- and -L-tryptophan, tryptamine, and serotonin (10). The maximal turnover number was obtained with L-tryptophan (99 mol min -mor of enzyme at 24°C), and the lowest value was with 5-hydroxy-L-tryp-tophan (20 p.Af). A marked substrate inhibition is observed by the L isomers of tryptophan and 5-hydroxytryptophan above 0.2 and 0.06 mM, at pH 6.6, respectively. The compounds including skatole, indole, in-doleacetic acid, 5-hydroxyindoleacetic acid, N-acetyltryptophan, melatonin, and a-methyl-DL-tryptophan, are all inert as substrate. 

Chiral complexes of amino acids and related ligands of type A and A [RuL(bipy)2]" (L = (-)-serine, (-)-tryptophane, 5-hydroxytryptophane, ° phenylalanine, (—)-alanine ) and [RuL(bipy)2] (L = ( —)-aspartate, (—)-glutamate ) have been reported. Inversion of the A and A isomers has been studied and equilibrium constants for the isomerization reactions deter-mined - . More recently, chiral complexes A, A-[Ru(L)2L ] (L = bipy, phen L H = S-threonine, 5-alio threonine) have been prepared and studied crystallographically. Reaction of [RuCl2(bipy)2] with 8-mercaptoquinoline (L) under basic conditions yields the N,S complex [RuL-(bipy)2l alkylation of the coordinated ligand at S has been achieved with Mel. ... 

Labetalol HCI 4-Benzyloxyanillne HCI Hydroxytryptophan N-Benzyloxycarbonyl-L-aspartic acid-Ct-nitrophenyl,0-benzyl diester Aspartame... 

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. 

Darmani, N. A. and Johnson, J. C. (2004) Central and peripheral mechanisms contribute to the antiemetic actions of delta-9-tetrahydrocannabinol against 5-hydroxytryptophan-induced emesis. Eur. J. Pharmacol, 488, 201-212. 

In conclusion, the deviation of the N(l)-0 bond from the indole molecular plane is responsible for the nucleophilic substitution reactions of the 1-hydroxytryptamine and 1-hydroxytryptophan derivatives. 

Davison, A. N. and Sandler, M., Inhibition of 5-hydroxytryptophan decarboxylase by phenylalanine metabolites. Nature 181, 186 (1958). 

D.L-tryptophan D,L-5-hydroxytryptophan D,L-kynurenine D,L-3-hydroxykynurenine D.L-5-hydroxykynurenine D,L-3-methoxykynurenine D,L-N-a-acetylkynurenine d, 1 -trisethylene-diaminc-cobalt(ni) complex... 

The majority of catecholamine and serotonin biosynthesis occurs within the nerve terminals by synthetic enzymes transported from the neuronal cell bodies. In all catecholamine neurons, the rate-limiting step in synthesis is conversion of tyrosine to dihydroxyphenylalanine by tyrosine hydroxylase. Dihydroxyphenylalanine is then converted to DA, norepinephrine, and epinephrine through a sequential process involving L-aromatic amino acid decarboxylase (conversion of dihydroxyphenylalanine to DA), dopamine-P-hydroxylase (conversion of DA to norepinephrine), and phenylethanol-amine-N-methyltransferase (conversion of norepinephrine to epinephrine). Cell-specific expression of these enzymes determines the main neurotransmitter for an individual catecholamine neuron. The synthesis pathway for serotonin involves a two-step process in which tryptophan hydroxylase first converts tryptophan to 5-hydroxytryptophan, which is then converted to... 

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