Phenylethylamines metabolism

Trace Amines. Figure 1 The main routes of trace amine metabolism. The trace amines (3-phenylethylamine (PEA), p-tyramine (TYR), octopamine (OCT) and tryptamine (TRP), highlighted by white shading, are each generated from their respective precursor amino acids by decarboxylation. They are rapidly metabolized by monoamine oxidase (MAO) to the pharmacologically inactive carboxylic acids. To a limited extent trace amines are also A/-methylated to the corresponding secondary amines which are believed to be pharmacologically active. Abbreviations AADC, aromatic amino acid decarboxylase DBH, dopamine b-hydroxylase NMT, nonspecific A/-methyltransferase PNMT, phenylethanolamine A/-methyltransferase TH, tyrosine hydroxylase. 

Several pathways are used for the aerobic degradation of aromatic compounds with an oxygenated C2 or C3 side chain. These include acetophenones and reduced compounds that may be oxidized to acetophenones, and compounds including tropic acid, styrene, and phenylethylamine that can be metabolized to phenylacetate, which has already been discussed. 

In the vertebrate CNS monoamines have been associated with a number of physiological functions (reviewed in Kandel et al., 1991). Serotonin has functions associated with mood, pain, sleep, learning, and memory. Dopamine has functions associated with schizophrenia, Parkinson s disease, and cocaine addiction. In vertebrates, dopamine is further metabolized into two additional neurotransmitters, norepinephrine and epinephrine. Norepinephrine increases the excitability of cells in response to sudden sensory input such as fear. Epinephrine has been identified in specific neurons of the brain, but the function of these cells is unknown. In addition, AADC has also been found in a class of neurons that do not have any of the four neurotransmitters discussed above (Jaeger et al., 1983). These neurons may use one of the trace amines, tyramine, tryptamine, or phenylethylamine, as a neurotransmitter. 

Monoamine oxidase inhibitors. The monoamine oxidase inhibitors (MAOIs) inhibit the intracellular catabolic enzyme monoamine oxidase. There are two types of monoamine oxidase MAO-A and MAO-B, both of which metabolize tyramine and dopamine. In addition, MAO-A preferentially metabolizes norepinephrine, epinephrine, and serotonin, and MAO-B preferentially metabolizes phenylethylamine (an endogenous amphetamine-like substance) and N-methylhistamine (Ernst, 1996). Some MAOIs are selective for A or B and some are nonselective (mixed). In addition, irreversible MAOIs (e.g., phenelzine, tranylcypromine) are more susceptible to the cheese effect than are the reversible agents (e.g., moclobemide). 

Monoamine oxidase A (MAO A) acts selectively on the substrates norepinephrine and serotonin, whereas monoamine oxidase B (MAO B) preferentially affects phenylethylamine. Both MAO A and MAO B oxidize dopamine and tyramine. MAO A inhibition appears to be most relevant to the antidepressant effects of these drugs. Drugs that inhibit both MAO A and MAO B are called non-selective. The MAOI antidepressants currently available in the United States are nonselective inhibitors. Because tyramine can be metabolized by either MAO A or MAO B, drugs that selectively inhibit one of these enzymes but not the other do not require dietary... 

MAOIs act by mitigating the actions of monoamine oxidase in the neuron and increasing monoamine content. There are two forms of monoamine oxidase. MAO-A is present in both dopamine and norepinephrine neurons and is found primarily in the brain, gut, placenta, and liver its primary substrates are norepinephrine, epinephrine, and serotonin. MAO-B is found primarily in serotonergic and histaminergic neurons and is distributed in the brain, liver, and platelets. MAO-B acts primarily on tyramine, phenylethylamine, and benzylamine. Both MAO-A and -B metabolize tryptamine and dopamine. 

Still another experimental route to introducing otherwise excluded molecules into the brain is to chemically modify them so that they are lipophilic and therefore can passively diffuse. The brain, just as most other organs and tissues of the body, has enzymes to metabolize or biotransform metabolites in order to use and then get rid of them. Many of these pathways are oxidative. A reduced species or derivative which is lipophilic can enter the brain by simple passive diffusion there to be oxidatively transformed into an active state. Compounds which have been tested in animals include derivatives of 2-PAM (an antidote for organophosphate insecticide poisoning) and phenylethylamine (similar to amphetamine type molecules). Figure 5 illustrates the general concept behind this method. 

Deuteriochloroform was the solvent of choice. The ft,ft-2H2 and , ,/ ,/ -2H4 phenylethylamine, m- and p-tyramine and tryptamine obtained3,4 have been used as tracers in metabolic studies and as internal standards in quantitative mass spectrometry3-5. 

As for adrenaline at least, an interruption on the entire respiratory metabolism may be observed, which is reflected on the chemoceptors of the carotid body by the variations of oxygen uptake and carbon dioxide production (148). The direct intervention on the chemoceptors of the carotid and aortic bodies only appears for the nicotinic substances and not for Pervitin (149). The natural sympathomimetics which possess a stimulating influence on the respiration are mainly ephedrine, hordenine, 0-phenylethylamine, and tyramine. 

Two isozymes, termed MAO A and MAO B, have been described. The early distinction between the two isozymes was based mainly on substrate selectivity and differential inhibition by various inhibitors . Serotonin and noradrenaline are preferentially deami-nated by MAO A, while benzylamine and phenylethylamine are better metabolized by MAO Dopamine and tyramine are equally deaminated by both isozymes. 

Amphetamine possesses an a-methyl group. As already mentioned at the beginning of this chapter, a-demethylation (to afford phenylethylamine or 2-phenyl-1-aminoethane in the case of amphetamine) results in agents with decreased lipophilicity and increased susceptibility to metabolism. Phenylethylamine lacks central stimulant activity. Homologation of the a-methyl group to, for example, an a-ethyl or a-n-propyl group results in a decrease or loss of central stimulant activity. The presence of the a-methyl group in amphetamine creates a chiral center hence, amphetamine exists as a pair of optical isomers. With respect to central stimulant actions, the S-(+)-isomer (i.e., dextroamphetamine) is several-fold more potent than its R-(-)- enantiomer (i.e., levamphetamine) this is not necessarily the case with other actions produced by amphetamine, particularly those produced in the periphery, such as its cardiovascular actions. 

Several of these amines are found in animals and some are involved in nerve transmission see Chapter 27). When plant amines are consumed by animals, they can be quite toxic. For example, phenylethylamine (8) in Acacia berlan-dieri is poisonous to livestock (Smith, 1977b). The presence of amines in foods consumed by humans also has been noted. Catecholamines, indoleamines, and histamine (11) fulfill important metabolic functions, especially in the nervous system and in the control of blood pressure. The occasional presence of greater than usual amounts of tyramine in cheese can cause severe episodes of hypertension, especially in the presence of monoamine oxidase inhibitors, which often are used in the treatment of depression (Smith, 1981). Amines can be formed from bacterial activity in foods (Smith, 1981). 

The symptomatic action of MAO-B inhibitors is mediated by blockade of the MAO-B enzyme involved in dopamine degradation, which results in increased dopamine availability at the synapse. This is not, however, the only mechanism of action. The symptomatic effect is also mediated by inhibition of amine uptake and a major increase in phenylethylamine concentrations in the striatum. Phenylethylamine is a trace amine which can amplify dopaminergic transmission. In addition, it has been proposed that blocking MAO-B metabolism of N-acetylated polyamine derivatives could modulate the activity of inhibitor glutamatergic efferents at the subthalamic level. The exact role of selegiline in amphetamine metabolism is not clearly understood. 

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