Oxidation monoamine

MAO Inhibitors. MAO is an enzyme which oxidizes a variety of monoamines. Among the substrates of this enzyme are tyramine, tryptamine, 5-hydroxytryptamine, histamine, and short chain aliphatic monoamines ( ). Oxidation of histamine to imidazoleacetaldehyde can be carried out by DAO as well as MAO. is also responsible for the conversion of N -MH, the product of HMT, to N -MIAA. Many MAO inhibitors have been identified they are conventionally divided into hydrazides, hydrazines and amines (44). Some MAO inhibitors, e.g. the hydrazines, are non-selective they also inhibit DAO. 

Suzuki O, Katsumata Y, Oyo M, et al. Inhibition of monoamine oxidate by hypericin. Plant Medica 1984 50 272-274. 

The opioid derivatives most commonly used as antitussives are dextromethorphan, codeine, levopropoxyphene, and noscapine (levopropoxyphene and noscapine are not available in the USA). While these agents (other than codeine) are largely free of the adverse effects associated with the opioids, they should be used with caution in patients taking monoamine oxide (MAO) inhibitors (see Table 31-5). Antitussive preparations usually also contain expectorants to thin and liquefy respiratory secretions. 

After reuptake of it NE is stored again or it is degraded. The major metabolic pathway of NE is its oxidation into 3,4-dihydroxymandelic acid by the type A of the enzyme monoamine oxidize (MAO). Numerous drugs have MAO as their primary target. Their can be divided into two groups non-reversible MAO inhibitors (MAOIs) and reversible MAO inhibitors (RIMAs). Respective examples for these groups are phenelzine and moclobemide (Blier and de Montigny 1985 Blier et al., 1986). 

Metabolism Monoamine oxidize A (Reversible) monoamine oxidize inhibitors (phenelsine, moclobemide, j)... 

Marley, E. Blackwell, B. Interactions of monoamine oxidate inhibitors, amines, and food stuffs. Adv Pharmacol and Chemo-Therap, 1970 8 185-239... 

Fig. 13. Formation of vanillylmandelic acid from norepinephrine and epinephrine [adapted from Gidow et ti. (G12)]. (a) Methylation of the amino group of norepinephrine (h) methylation through catechol-O-methyltransferase and (c) monoamine oxidation + aldehyde oxidation.

Based on a series of elegant studies on the enzymic and nonenzymic oxidation of amines and substrate analogs, Silverman and co-workers proposed that the mechanism of irreversible inactivation and substrate utilization by MAO is mediated through radical intermediates (95). Precedence for this mechanism is based on the electrochemical oxidation of amines, which is believed to proceed through the radical cation intermediate 22 (Scheme 16) (96-98). Thus, the corresponding mechanism for monoamine oxidation by MAO requires two one-electron transfers from the substrate to flavin (Scheme 17, compounds 23 and 24). Enzymic reaction is initiated by slow electron transfer of an amine non-bonded electron to the flavin cofactor, producing the amine radical cation 23 and the flavin semiquinone radical. Formation of the amine radical cation facilitates loss of the a-proton, thereby avoiding the removal of nonacidic protons that would be necessary in a carbanionic mechanism. Subsequent electron... 

Scheme 17. Mechanism for MAO-catalyzed monoamine oxidation proposed by Silverman (95).

The observed higher values of monoacetylcadaverine and mono-propionylcadaverine in the blood of some schizophrenic patients could therefore be caused by an inefficient monoamine oxidizing system. Several studies have indicated that an altered activity of blood platelet monoamine oxidase accompanies mental illness (16, 24). 

The next significant strength improvement followed the 1950 Du Pont (19) discovery of monoamine and quaternary ammonium modifiers, which, when added to the viscose, prolonged the life of the ziac cellulose xanthate gel, and enabled even higher stretch levels to be used. Modifiers have proliferated siace they were first patented and the Hst now iacludes many poly(alkylene oxide) derivatives (20), polyhydroxypolyamines (21—23), and dithiocarbamates (24). 

Histamine AND histamine antagonists). It is formed from histidine by the enzyme L-histidine decarboxylase. In the periphery, histamine is stored ia mast cells, basophils, cells of the gastric mucosa, and epidermal cells. In the CNS, histamine is released from nerve cells and acts as a neurotransmitter. The actions of histamine ate terrninated by methylation and subsequent oxidation via the enzymes histamine-/V-methyltransferase and monoamine oxidase. 

Monoamine Oxidase Inhibitors. MAOIs inactivate the enzyme MAO, which is responsible for the oxidative deamination of a variety of endogenous and exogenous substances. Among the endogenous substances are the neurotransmitters, norepinephrine, dopamine, and serotonin. The prototype MAOI is iproniazid [54-92-2] (25), originally tested as an antitubercular dmg and a close chemical relative of the effective antitubercular, isoniazid [54-85-3] (26). Tubercular patients exhibited mood elevation, although no reHef of their tuberculosis, following chronic administration of iproniazid. In... 

Copper is one of the twenty-seven elements known to be essential to humans (69—72) (see Mineral nutrients). The daily recommended requirement for humans is 2.5—5.0 mg (73). Copper is probably second only to iron as an oxidation catalyst and oxygen carrier in humans (74). It is present in many proteins, such as hemocyanin [9013-32-3] galactose oxidase [9028-79-9] ceruloplasmin [9031 -37-2] dopamine -hydroxylase, monoamine oxidase [9001-66-5] superoxide dismutase [9054-89-17, and phenolase (75,76). Copper aids in photosynthesis and other oxidative processes in plants. 

Two important pathways for catecholamine metaboHsm are 0-methylation by COMT, which is cytoplasmicaHy localized, and oxidative deamination by the mitochondrial localized enzyme MAO. There are large amounts of MAO in tissues such as the fiver and the heart which are responsible for the removal of most of the circulating monoamine, including some taken in from the diet. Tyramine is found in high concentrations in certain foods such as cheese, and in wine. Normally, this tyramine is deaminated in the fiver. However, if MAO is inhibited, the tyramine may then be converted into octopamine [104-14-37] which may indirecdy cause release of NE from nerve terminals to cause hypertensive crisis. Thus MAO, which is relatively nonspecific, plays an important role in the detoxification of pharmacologically active amines ingested from the diet. 

Ubiquitous mitochondrial monoamine oxidase [monoamine oxygen oxidoreductase (deaminating) (flavin-containing) EC 1.4.3.4 MAO] exists in two forms, namely type A and type B [ monoamine oxidase (MAO) A and B]. They are responsible for oxidative deamination of primary, secondary, and tertiary amines, including neurotransmitters, adrenaline, noradrenaline, dopamine (DA), and serotonin and vasoactive amines, such as tyramine and phenylethylamine. Their nonselec-tive and selective inhibitors ( selective MAO-A and -B inhibitors) are employed for the treatment of depressive illness and Parkinson s disease (PD). 

Recently Turner and coworkers have sought to extend the deracemization method beyond a-amino acids to encompass chiral amines. Chiral amines are increasingly important building blocks for pharmaceutical compounds that are either in clinical development or currently licensed for use as drugs (Figure 5.7). At the outset of this work, it was known that type II monoamine oxidases were able to catalyze the oxidation of simple amines to imines in an analogous fashion to amino acid oxidases. However, monoamine oxidases generally possess narrow substrate specificity and moreover have been only documented to catalyze the oxidation of simple, nonchiral... 

Medvedev AE, Veselovsky AV, Shvedov VI, Tikhonova OV, Moskvitina TA, Fedotova OA, et al. Inhibition of monoamine oxidase by pirlindole analogues 3D-QSAR and CoMFA analysis. / Chem Inf Comput Sci 1998 38 1137-44. Miller JR, Edmondson DE. Structure-activity relationships in the oxidation of para-substituted benzylamine analogues by recombinant human liver monoamine oxidase A. Biochemistry 1999 38 13670-83. 

This can be carried out in vitro (in brain slices, cultured cell preparations) or in vivo and involves penetrating the experimental tissue with a carbon-fibre electrode of 5-30 pm in diameter (Fig. 4.9). This serves as an oxidising electrode and the Faradaic current generated by the oxidation of solutes on the surface of the electrode is proportional to their concentration. Obviously, only neurotransmitters which can be oxidised can be measured in this way so the technique is mainly limited to the study of monoamines and their metabolites. The amplitude of each peak on the ensuing voltammogram is a measure of solute concentration and individual peaks can be identified because different... 

The beneficial effect of deprenyl in Parkinson s disease was su ested to be in part due to its effect on increasing the levels of SOD activity in several brain regions (Carrillo et al., 1993). Deprenyl is known to inhibit monoamine oxidase type B, which results in a reduction in hydrogen peroxide formation by blockade of the oxidative deamination of dopamine. That is believed to be the major mechanism of action of this drug in inhibiting the progression of Parkinson s disease. 

Marker, H.S., Weiss, C., Silides, D.J., and Cohen, G. (1981). Coupling of dopamine oxidation (monoamine oxidase activity) to glutathione oxidation via the generation of hydrogen peroxide in rat brain homogenates. J. Neurochem. 36, 589-593. 

It is premature to define the exact mechanism by which DA is involved in the response to METH or MDMA. It is known- that these drugs release large quantities of DA and that DA can be readily oxidized to reactive metabolites, which could possibly cause destruction of nerve terminals (Graham 1978 Maker et al. 1986). Moreover, these effects could be enhanced by inhibition of monoamine oxidase, which is known to occur with these drugs (Susuki et al. 1980). The possibility that 6-DOHA is formed and subsequently destroys the nerve terminals, as suggested by Seiden and Vosmer (1984), also requires investigation. 

Fuller, R.W. Serotonin oxidation by rat brain monoamine oxidase Inhibition by 4-chloroamphetamine. Life Sci 5 2247-2252, 1966. 

The assessment of clearance is complicated by the numerous mechanisms by which compounds may be cleared from the body. These mechanisms include oxidative metabolism, most commonly by CYP enzymes, but also in some cases by other enzymes including but not limited to monoamine oxidases (MAO), flavin-containing monooxygenases (FMO), and aldehyde oxidase [45, 46], Non-oxidative metabolism such as conjugation or hydrolysis may be effected by enzymes such as glucuronyl transferases (UGT), glutathione transferases (GST), amidases, esterases, or ketone reductases, as well as other enzymes [47, 48], In addition to metabolic pathways, parent compound may be excreted directly via passive or active transport processes, most commonly into the urine or bile. 

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... 

---