Monoamine oxidase inactivation

As mentioned, the mildness of NaBHaCN (coupled with its effectiveness and stability in aqueous media) has attracted considerable interest for applications in biochemical areas. Examples include the trapping of suspected imine intermediates produced in enzyme (mitochondrial monoamine oxidase) inactivation by amines, the establishment by reduction of the positions of imine-forming amines in 2-keto-3-deoxy-6-phosphogluconate aldolase, and the transfer labeling of methionyl-tRNA synthetase and methionyl-tRNA transformalase by treatment with periodate-treated tRNA. In fact, most biochemical applications of NaBHaCN have utilized in situ imine formation-reduction (i.e. reductive amination) conditions and will be further discussed in Section 1.2.2.3.1. 

E. Relationship between Active Site Geometry and Inhibitor Structure in Defining Site of Covalent Bond Formation in Monoamine Oxidase Inactivation... 

Secondary amines such as A-cyclopropylbenzylamine (A-CBA) are also inactivators of monoamine oxidase. Inactivation by iV-[o c/opropy/- H]N-CBA re-... 

Monamine Oxidase Inhibitors (MAOI). The enzyme monoamine oxidase inactivates norepinephrine, dopamine, epinephrine, and serotonin. By inhibiting monoamine oxidase, the levels of these neurotransmitters rise. Examples of these drugs includes isocarboxazid (Marplan), phenelzine sulfate (Nardil), and tranycypromine sulfate (Parnate). 

Van Houten KA, Kim JM, Bogdan MA, Feni DC, Mariano PS. A new strategy for the design of monoamine oxidase inactivators. Exploratory studies with tertiary allylic and propargylic amino alcohols. J Am Chem Soc 1998 120 5864-5872. 

Other types of biological oxidation are catalyzed by more specific enzymes, which play an individual role in the metabolism (various specific dehydrogenases and oxidases) or in regulatory processes (e.g. monoamine oxidase inactivating some neurotransmitters) rather than coping with xenobiotics. However, many of these enzymes are soluble and may be present in the body fluids and come into contact with components even in the extracellular compartment. 

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... 

Isoproterenol is given sublingually or by iv. It is metabolized by monoamine oxidase and catechol-0-methyltransferase in brain, Hver, and other adrenergically innervated organs. The pharmacological effects of isoproterenol are transient because of rapid inactivation and elimination. About 60% is excreted unchanged. Adverse effects using isoproterenol therapy include nervousness, hypotension, weakness, dizziness, headache, and tachycardia (86). 

Monoamine oxidase (MAO) inactivates serotonergic and catecholaimnergic neurotransmitters MAO (A and B) inhibitors exhibit mood elevatmg properties 5-Fluoro-Ot-methyltryptamine 19) is an important MAO A-seleUive inhibitor In the treatment of certam depressive illnesses, 4-fluorotranylcypromine (20b) is 10 tunes more potent than the parent tranylcypromme (TCP, 20a) The enhanced m vivo activity may be due to increased lipophihcity at20b and/or to blockade of metabohc para hydroxylation [52]... 

Oxazolidinones and dihydrofuranones as inactivators and substrates of monoamine oxidase B, approaches to the design of antiparkinsonian agents 97F343. 

Epinephrine is administered by a variety of different routes in anaphylaxis, except for the oral route, which is not feasible because of rapid inactivation of epinephrine in the gastrointestinal tract by catechol-O-methyltransferase and monoamine oxidase [9]. The initial intramuscular epinephrine doses of 0.3-0.5 mg currently recommended for adults with anaphylaxis are low compared with the doses required for resuscitation following cardiac arrest [1, 2,4,18]. 

Figure 20.1 Schematic diagram illustrating how antidepressants increase the concentration of extraneuronal neurotransmitter (noradrenaline and/or 5-HT). In the absence of drug (b), monoamine oxidase on the outer membrane of mitochondria metabolises cytoplasmic neurotransmitter and limits its concentration. Also, transmitter released by exocytosis is sequestered from the extracellular space by the membrane-bound transporters which limit the concentration of extraneuronal transmitter. In the presence of a MAO inhibitor (a), the concentration of cytoplasmic transmitter increases, causing a secondary increase in the vesicular pool of transmitter (illustrated by the increase in the size of the vesicle core). As a consequence, exocytotic release of transmitter is increased. Blocking the inhibitory presynaptic autoreceptors would also increase transmitter release, as shown by the absence of this receptor in the figure. In the presence of a neuronal reuptake inhibitor (c), the membrane-bound transporter is inactivated and the clearance of transmitter from the synapse is diminished...

The primary mechanism used by cholinergic synapses is enzymatic degradation. Acetylcholinesterase hydrolyzes acetylcholine to its components choline and acetate it is one of the fastest acting enzymes in the body and acetylcholine removal occurs in less than 1 msec. The most important mechanism for removal of norepinephrine from the neuroeffector junction is the reuptake of this neurotransmitter into the sympathetic neuron that released it. Norepinephrine may then be metabolized intraneuronally by monoamine oxidase (MAO). The circulating catecholamines — epinephrine and norepinephrine — are inactivated by catechol-O-methyltransferase (COMT) in the liver. 

HA turnover is rapid in the brain, with a half-life of about 30 min. This can change very quickly depending on neuronal activity. There is no high-affinity uptake system for HA once released, HA is inactivated by catabolism. In the brain, released HA is methylated almost exclusively by the enzyme histamine-N-methyltransferase (E.C. 2.1.1.8). The tele-methyl-HA is subsequently degraded by monoamine oxidase-B (MAO-B) and aldehyde dehydrogenase to produce tele-methylimidazoleacetic acid (Brown et ah, 2001). 

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. 

Monoamine oxidase and catechol- O-methyltransferase are primarily responsible for the inactivation of catecholamines 214... 

Salach JI, Singer TP, Castagnoli N, Jr, et al. Oxidation of the neurotoxic amine l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) by monoamine oxidases A and B and suicide inactivation of the enzymes by MPTP. Biochem Biophys Res Commun 1984 125(2) 831-835. 

MAO (monoamine oxidase) two related enzymes that inactivate neurotransmitters such as serotonin, dopamine, and norepinephrine. 

Blocking Enzymes. Remember that there are enzymes both in the synapse and in the cytoplasm of the nerve cells that metabolize and thereby inactivate neurotransmitter molecules. One way to promote neurotransmission is to increase the supply of available neurotransmitter. Blocking (or inhibiting) the enzymes that destroy neurotransmitter will do just that. Certain antidepressants known as monoamine oxidase inhibitors (MAOIs) and some medications used to treat Alzheimer s disease act in this manner. 

A third way of promoting norepinephrine activity is to interfere with the enzyme that inactivates norepinephrine, monoamine oxidase (MAO). The monoamine oxidase inhibitors (MAOIs) work in this way. Incidentally, inhibiting monoamine oxidase also increases serotonin and dopamine activity. 

The process of oxidative deamination is the most important mechanism whereby all monoamines are inactivated (i.e. the catecholamines, 5-HT and the numerous trace amines such as phenylethylamine and tryptamine). Monoamine oxidase occurs in virtually all tissues, where it appears to be bound to the outer mitochondrial membrane. Whereas there are several specific and therapeutically useful monoamine oxidase inhibitors, inhibitors of catechol-O-methyltransferase have found little application. This is mainly due to the fact that at most only 10% of the monoamines released from the nerve terminal are catabolized by this enzyme. The main pathways involved in the catabolism of the catecholamines are shown in Figure 2.16. 

The effect of released norepinephrine wanes quickly, because approx. 90% is actively transported back into the axoplasm, then into storage vesicles (neuronal re-uptake). Small portions of norepinephrine are inactivated by the enzyme catechol-0-methyltransferase (COMT, present in the cytoplasm of postjunctional cells, to yield normeta-nephrine), and monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells, to yield 3,4-dihydroxymandelic acid). 

Monamines are inactivated into aldehydes by amine oxidase (monoamine oxidase, MAO ) with deamination and simultaneous oxidation. MAO inhibitors therefore play an important role in pharmacological interventions in neurotransmitter metabolism. 

R.B. Silverman, W.P. Flawe, SAR studies of fluorine-substituted benzylamines and substituted 2-phenylethylamines as substrates and inactivators of monoamine-oxidase-B, J. Enzyme Inhib. 9 (1995) 203-215. 

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