Oxidation of Serotonin

Wrona, M.Z., Dryhurst, G. Oxidation of serotonin by superoxide radical implications to neurode-generative brain disorders. Chem. Res. Toxicol. 11 639, 1998. 

In the late 1960s, different types of cyclopropylamines, the A/-substituted cyclopropylamines, were reported [111]. One of the most interesting compounds in the new class was A/-[2-o-chlorophenoxy]-ethyl]-cyclopropylamine (Lilly 51641) (42). This compound noncompetitively inhibited the MAO-catalyzed oxidation of serotonin, tyramine, phenylethylamine, and tryptamine in vitro and increased the serotonin concentration in the whole rat brain in vitro. In structure-activity studies on a series of m- and p-aromatic substituted A/-(phenoxyethyl)cyclopropylamines (43), the degree of inhibition correlated well with a and % values [112]. 

Wrona, M.Z. Yang, Z. McAdams, M. O Connor-Coates, S. and Dryhurst, G. Hydroxyl radical-mediated oxidation of serotonin Potential insights into the neurotoxicity of methamphetamine. J Neurochem 64 1390-1400, 1995. 

Thiersch, J. B., Histamine and histaminase in chronic myeloid leukemia of man I. Histamine in the blood of chronic myeloid leukemia. Oxidation of serotonin in the presence of ceruloplasmin, Chem. Abstr. 42, 4268 (1948). 

The first stage in the oxidation of serotonin is probably catalyzed by monoamine oxidase. This enzyme is present in mitochondria (373) and also as a soluble protein 374). The soluble fraction from guinea pig liver, purified ten- to fifteenfold, converted serotonin to 5-hydroxyindoleacetic acid. The enzyme requires DPN and another prot fraction to form the latter product. The over-all reaction is believed to be... 

Against this backdrop, researchers reported evidence that iproniazid, the antitubercular drug that was to become the first antidepressant, might increase norepinephrine and serotonin levels in the brain. How did it have this effect Recall that some of the neurotransmitter molecules released by a neuron are destroyed by enzymes in the synaptic cleft between the sending presynaptic neuron and the receiving postsynaptic neuron. When the neurotransmitter is a monoamine - like norepinephrine and serotonin - this process is called monoamine oxidase (MAO). As early as 1952 researchers at the Northwestern University Medical School in Chicago reported that iproniazid inhibited the oxidation of monoamines. This meant that iproniazid was a... 

Here then is the logic behind the first version of the chemical-imbalance theory. Iproniazid is a monamine oxidase inhibitor - it inhibits the oxidation of norepinephrine and serotonin in the synapses, thereby leaving more of these neurotransmitters available in the brain. When depressed people take iproniazid, they get better. Therefore insufficient norepinephrine and/or serotonin causes depression.12... 

Figure 15.14 illustrates a typical voltammetric result for the determination of dopamine in the presence of ascorbic acid with a CNT-modified electrode. The selective voltammetric detection of uric acid [82] or norepinephrine [83] in the presence of ascorbic acid has been demonstrated with a (3-cyclodextrin-modified electrodes incorporating CNTs. Ye et al. [84] have studied the electrocatalytic oxidation of uric acid and ascorbic acid at a well-aligned CNT electrode, which can be used for the selective determination of uric acid in the presence of ascorbic acid. The simultaneous determination of dopamine and serotonin on a CNT-modified GC electrode has also been described [85],... 

An electrochemical sensor using an array microelectrode was tested for the detection of allergens such as mite and cedar pollen (Okochi et ah, 1999). Blood was used in the assay and the release of serotonin, a chemical mediator of allergic response, which is electrochemically oxidized at the potential around 300 mV, was monitored for electrochemical detection by cyclic voltammetry. 

Chiavegatto S, Nelson RJ (2003) Interaction of nitric oxide and serotonin in aggressive behavior. Horm Behav 44 233-241... 

Gammie SC, Nelson RJ (1999) Maternal aggression is reduced in neuronal nitric oxide synthase-deficient mice. J Neurosci 19 8027-8035 Caspar P, Cases O, Maroteaux L (2003) The developmental role of serotonin news from mouse molecular genetics. Nat Rev Neurosci 4 1002-1012 Gobbi G, Murphy DL, Lesch K, Blier P (2001) Modifications of the serotonergic system in mice lacking serotonin transporters an in vivo electrophysiological study. J Pharmacol Exp Ther 296 987-995... 

The enzymes responsible for the metabolism of serotonin are present in all of the cells containing this amine and in the Uver. Serotonin is initially oxidatively deami-nated to form 5-hydroxyindoleacetaldehyde this compound is subsequently rapidly oxidized to the major metabolite 5-hydroxyindoleacetic acid, which is excreted in the urine. Much of the serotonin released in the brain at synapses is taken back into the initial neuron by an active reuptake mechanism to be released again. 

Most SSRls inhibit cytochrome P450 (CYP) isoenzymes, a family of about 30 enzymes that catalyze the oxidase metabolism of multiple dmgs in humans. They are eliminated mostly through hepatic metabolism by oxidase demethylation or oxidative deamination. SSRls generally act by inhibiting the pumps that send serotonin across synapses, thus locally increasing the levels of serotonin in those synapse spaces. However, it is important to point out from the onset that the responses... 

Asano, S., Matsuda, T., Nakasu, Y, Maeda, S., Nogi, H., and Baba, A. (1997) Inhibition by nitric oxide of the uptake of [3H]serotonin into rat hrain synaptosomes.J Pharmacol 75 123-128. 

The alkaloids are also relevant to drug design. Alkaloids are complex heterocyclic compounds that contain nitrogen and thus have base-like (hence the term alkaloid ) properties they are extremely structurally diverse. Nicotine is one of the simplest alkaloids. Oxidation of nicotine produces nicotinic acid, a vitamin that is incorporated into the important coenzyme nicotinamide adenine dinucleotide, commonly referred to as NAD" (oxidized form). The neurotransmitter serotonin is an alkaloid containing the aromatic indole ring system. 

There is good evidence that propofol exerts an anti-emetic effect. The mechanism of this is unclear, but animal studies have shown that it may involve depleting the area postrema of serotonin as well as direct GABA-mediated inhibition, or inhibition of dopamine release in the brain. This probably requires a plasma concentration of over 350 ng-mL-1, and therefore will be seen when propofol is used as an induction agent for very short cases, or when it is used as an infusion in longer cases. Nitrous oxide... 

Serotonin is metabolized by MAO, and the intermediate product, 5-hydroxyindoleacetaldehyde, is further oxidized by aldehyde dehydrogenase to 5-hydroxyindoleacetic acid (5-HIAA). In humans consuming a normal diet, the excretion of 5-HIAA is a measure of serotonin synthesis. Therefore, the 24-hour excretion of 5-HIAA can be used as a diagnostic test for tumors that synthesize excessive quantities of serotonin, especially carcinoid tumor. A few foods (eg, bananas) contain large amounts of serotonin or its precursors and must be prohibited during such diagnostic tests. 

And it may play such a role here. When one balances the sort-of stimulant nature of a-MT with the potent psychedelic properties of a,0-DMS, one can ask if the oxidation of the tryptamine system at this 5-position can be of some significance. Tryptamine becomes serotonin by this action. DMT becomes bufotenine by this action. If there is some extension of this to the a-MT world, then the placement of a fluoro group at that position of attack would be interesting. 5-F-a-MT has been made, and it appears to be of reduced activity in man. But it has proven to be an extremely potent monoamineoxidase inhibitor, and strongly influences the brain serotonin levels. The 6-fluoro isomer, 6-F-a-MT, is also effective. 

The biological function of amine oxidases involves the oxidation of biogenic amines formed during normal biological processes. In mammals, the monoamine oxidases are involved in the control of the serotonin catecholamine ratios in the brain, which in turn influence sleep and EEG patterns, body temperature, and mental depression. Two groups of amine oxidases are involved in the oxidative deamination of naturally occurring amines as well as foreign compounds. 

On account of the activity of these plant extracts and the isolation from them of iV,iV-dimethyltryptamine, the physiological activity of this base in humans is of interest. When injected intramuscularly, it causes hallucinations and illusions, which are characterized by their rapid appearance and brief duration (80). Apparently, dimethyltrypt-amine is rapidly metabolized and excreted mainly as indoleacetic acid, although the urine is enriched with 5-hydroxyindoleacetic acid whether this is the result of oxidation at the 5-position or stimulation of the metabolism of serotonin in the brain is not yet known (80). 

Carbolines exert a variety of pharmacological effects, including sedation, catalepsy, inhibition of convulsion, hallucination, and inhibition of monoamine oxidases (MAO) and of monoamine uptake (104a,b). Extensively investigated was the inhibition of MAO by /3-carbolines, which is probably responsible for their antidepressant effects in man (5d). p-Caibolines inhibit the oxidative deamination of serotonin at micromolar... 

In rats, high doses of vitamin Be (10 mg per kg of body weight) lead to decreased oxidative metabolism of tryptophan, presumably as a result of impaired responsiveness to glucocorticoid hormones, an increased plasma concentration of tryptophan, and increased uptake of tryptophan into the brain, leading to an increased rate of serotonin turnover (Bender and Totoe, 1984a). This suggests that vitamin Bg supplements might be a useful adjunct to tryptophan for the treatment of depression. 

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