Monoamine inactivation, mechanisms

Studies on monoamine inactivation mechanisms in insects have yielded equivocal results with N-acetylation (6-9), oxidative deamination (10,11) and -sulphate or 6-alanyl conjugation (12,13) proposed as possible routes of monoamine catabolism however, the weight of evidence favours N-acetylation as the principal mechanism of monoamine breakdown Sodium-sensitive and sodium-insensitive uptake mechanisms for OA have also been described in the cockroach central nervous system (14). 

Discovery. The majority of both old and new antidepressants act by virtue of their ability to inhibit monoamine transporter mechanisms in the brain. The concept that neurotransmitters are inactivated by uptake of the released chemical into the nerve terminal from which it had been released or into adjacent cells is less than 40 years old. Before this it was generally assumed that the inactivation of norepinephrine and the other monoamine neurotransmitters after their release from nerves was likely to involve rapid enzymatic breakdown, akin to that seen with acetylcholinesterase. The degradation of monoamines by the enzyme monoamine oxidase vas known early on, and in the 1950s a second enzyme catechol-O-methyl transferase (COMT) vas discovered and was thought to play a key role in inactivating norepinephrine and other catecholamines. 

F. New Classes of Monoamine Oxidase Mechanism-Based Inactivators Direct... 

D. Reactivation of A-CBA-1nactivated Monoamine Oxidase Revised Inactivation Mechanism for A-Cyclopropylarylalkylamines... 

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. 

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. 

Inhibitors of monoamine oxi-dase-B (MAOb). This isoenzyme breaks down dopamine in the corpus striatum and can be selectively inhibited by selegiline. Inactivation of norepinephrine, epinephrine, and 5-HT via MAOa is unaffected. The antiparkinsonian effects of selegiUne may result from decreased dopamine inactivation (enhanced levodopa response) or from neuroprotective mechanisms (decreased oxyradical formation or blocked bioactivation of an unknown neurotoxin). 

These reactions, which have provided a means of inhibiting the flavin-linked monoamine oxidases, enable us to end on a clinical note. The monoamine oxidases are responsible for the deamination of monoamines such as adrenaline, noradrenaline, dopamine, and serotonin, which act as neurotransmitters. Imbalances in the levels of monoamines cause various psychiatric and neurological disorders Parkinson s disease is associated with lowered levels of dopamine, and low levels of other monoamines are associated with depression. Inhibitors of monoamine oxidases may consequently be used to treat Parkinson s disease and depression. The flavin moiety is covalently bound to the enzyme by the thiol group of a cysteine residue (equation 9.17). The acetylenic suicide inhibitor N,N-dimethyl-propargylamine inactivates monoamine oxidases by alkylating the flavin on N-5.25 A likely mechanism for the reaction is the Michael addition of the N-5 of the reduced flavin to the acetylenic carbon 2... 

Polasek TM, Elliot DJ, Somogyi AA, et al. An evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid. Br J Clin Pharmacol 2006 61(5) 570-584. 

The effect of released norepinephrine wanes quickly, because -90% is transported back into the axoplasm by a specific transport mechanism (norepinephrine transporter, NAT) and then into storage vesicles by the vesicular transporter (neuronal reuptake). The NAT can be inhibited by tricyclic antidepressants and cocaine. Moreover, norepinephrine is taken up by transporters into the effector cells (extraneuronal monoamine transporter, EMT). Part of the norepinephrine undergoing reuptake is enzymatically inactivated to normetanephrine via catecholamine O-methyltransferase (COMT, present in the cytoplasm of postjunctional cells) and to dihydroxymandelic acid via monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells). 

After the initial discovery that 0-fluoromethylene-substituted amines (e.g., 184, Table 1) were potent, mechanism-based inhibitors of monoamine oxidase (MAO) (41), the concept was successfully broadened to include most of the common amine oxidases (Table 1). This approach was also used to design inhibitors of y-aminobutyric acid transaminase both the a- and 0- substituted amino acids 189 and 190 were found to inactivate this enzyme. Recently, applica-tion of this concept to the design of inhibitors of S-adenosyl-homocysteine hydrolase (SAH) has led to the discovery of very potent inhibitors of this enzyme (e.g., 176, Table 1). 

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... 

Fig. 19. Mechanism proposed for inactivation of monoamine oxidase by 3-dimethylamino-1-propyne.

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