Monoamine oxidase A

Dopamine. Dopamine (DA) (2) is an intermediate in the synthesis of NE and Epi from tyrosine. DA is localized to the basal ganglia of the brain and is involved in the regulation of motor activity and pituitary hormone release. The actions of DA are terminated by conversion to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase-A and -B (MAO-A and -B) in the neuron following reuptake, or conversion to homovanillic acid (HVA) through the sequential actions of catechol-0-methyl transferase (COMT) and MAO-A and -B in the synaptic cleft. 

Treatment of Major Depression. Dmgs commonly used for the treatment of depressive disorders can be classified heuristicaHy iato two main categories first-generation antidepressants with the tricycHc antidepressants (TCAs) and the irreversible, nonselective monoamine—oxidase (MAO) inhibitors, and second-generation antidepressants with the atypical antidepressants, the reversible inhibitors of monoamine—oxidase A (RIMAs), and the selective serotonin reuptake inhibitors (SSRIs). Table 4 fists the available antidepressants. 

The TCAs, such as amitriptyline (Elavil) and dox-epin (Sinequan), inhibit reuptake of norepinephrine or serotonin at the presynaptic neuron. Drug classified as MAOIs inhibit the activity of monoamine oxidase a complex enzyme system that is responsible for breaking down amines. This results in an increase in endogenous epinephrine, norepinephrine and serotonin in the nervous system. An increase in these neurohormones results in stimulation of the CNS. The action of the SSRIs is linked to their inhibition of CNS neuronal uptake of serotonin (a CNS neurotransmitter). The increase in serotonin levels is thought to act as a stimulant to reverse depression. 

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. 

Reck F, Zhou F, Girardot M, Kern G, Eyermann CJ, Hales NJ, et al. Identification of 4-substituted 1,2,3-triazoles as novel oxazolidinone antibacterial agents with reduced activity against monoamine oxidase A. J Med Chem 2005 48 499-506. 

Saura, J, Bleuel, Z, Ulrich, J, Mendelowitsch, A, Chen, K, Shih, JC, Malherbe, P, Da Prada, M and Richards, JG (1996) Molecular neuroanatomy of human monoamine oxidases A and B revealed by quantitative enz5mie radioautoradiography and in situ hybridization histochemistry. Neurosci. 70 755-774. 

Yoshida, K. et al. (2002). Monoamine oxidase a gene polymorphism, tryptophan hydroxylase gene polymorphism and antidepressant response to fluvoxamine in Japanese patients with major depressive disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry, 26, 1279-83. 

Cusin, C., Serretti, A., Zanardi, R. etal. (2002). Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity. Int.. Neuropsychopharmacol, 5, 27-35. 

Berlin, I.S.S., Spreux-Varoquaux, O., Launay, J.M., Olivares, R., Millet, V., Lecrubier, Y., Puech, A.J. A reversible monoamine oxidase A inhibitor (moclobemide) facilitates smoking cessation and abstinence in heavy, dependent smokers. Clin. Pharmacol. Ther. 58 444, 1995. 

Berlin, I., Spreux-Varoquaux, O., Said, S., Launay, 1. Effects of past history of major depression on smoking characteristics, monoamine oxidase-A and -B activities and withdrawal symptoms in dependent smokers. Drug Alcohol Depend. 45 31, 1997. 

MAOI non-selective monoamine oxidase (A/B) inhibitors RIMA reversible inhibitor of monamine oxidase type A SSRI selective serotonin (5-HT) reuptake inhibitors SNRI serotonin/noradrenaline reuptake inhibitor SNARI selective noradrenaline (NA) reuptake inhibitor NA = 5-HT — DA potency of the drug is very similar in raising the level of both (or all three) monamines NA > 5-HT more selective for NA 5-HT>NA more selective for 5-HT NA increases the release of NA. 

Isoenzymes Structurally related enzyme proteins that catalyse very similar or identical reactions (e.g., monoamine oxidase A and B, cytochrome P-450). 

Other knockout models that could be used to validate candidate genes include mice that lack monoamine oxidase A (MAO-A), which have demonstrated altered behavior and alcohol tolerance [54]. Transgenic mice in which the dopamine transporter gene has been deleted show striking hyperactivity via enhanced persistence of dopamine which is not altered by cocaine or amphetamine administration [55]. Knockouts of the serotonin IB receptor are also available and are best used as models of vulnerability to drug abuse [56]. 

Bach AW, Lan NC, Johnson DL, et al. cDNA cloning of human liver monoamine oxidase A and B molecular basis of differences in enzymatic properties. Proc Natl Acad Sci USA 1988 85(13) 4934—4938. 

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. 

Beriin I, Said S, Spreux-Varoquaux 0, Launay JM, Oiivares R, Miiiet V, Lecrubier Y, Puech AJ. (1995). A reversibie monoamine oxidase A inhibitor (mociobemide) faciiitates smoking cessation and abstinence in heavy, dependent smokers. Clin Pharmacol Ther. 58(4) 444-52. 

Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, Shea C, Alexoff D, MacGregor RR, Schlyer DJ, Zezulkova I, Wolf AP. (1996b). Brain monoamine oxidase A inhibition in cigarette smokers. Proc Natl Acad Sci USA. 93(24) 14065-9. 

Hauptmann N, Grimsby J, Shih JC, Cadenas E. 1996. The metabolism of tyramine by monoamine oxidase A/B causes oxidative damage to mitochondrial DNA. Arch Biochem... 

Agatsuma S, Lee M, Zhu H, Chen K, Shih 1C, Seif I, Hiroi N (2006) Monoamine oxidase A knockout mice exhibit impaired nicotine preference but normal responses to novel stimuli. Hum Mol Genet 15 2721-2731... 

Guillem K, VouiUac C, Azar MR, Parsons LH, Koob GF, Cador M, Stinus L (2006) Monoamine oxidase A rather than monoamine oxidase B inhibition increases nicotine reinforcement in rats. Eur J Neurosci 24 3532-3540... 

Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, Young T, Praschak-Rieder N, Wilson AA, Houle S (2006) Elevated monoamine oxidase a levels in the brain an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 63 1209-1216... 

BDNF, brain-derived neurotrophic factor DAT, dopamine transporter DRD, dopamine receptor MAOA, monoamine oxidase A MB-catechol-O-methyltransferase QM-MSP, quantitative multiplex methylation-specific polymerase chain reaction RELN, reelin TH. These primers are suitable for QM-MSP. 

Two enzymes are concerned in the metabolism of catecholamines, namely monoamine oxidase, which occurs mainly intraneuronally, and catechol-O-methyltransferase, which is restricted to the synaptic cleft. The importance of the two major forms of monoamine oxidase, A and B, will be considered elsewhere. 

Monoamine Oxidase A MAOA Inhibition May induce severe hypertensive crisis (known as the Cheese reaction ) - Centrally mediated side effects such as the serotonin syndrome, dizziness, blurred vision and weakness. 

Beyond their action upon SERT and NET, venlafaxine (1), milnacipran (2) and duloxetine (3) are remarkably selective molecules. All three of them have displayed very low in vitro affinity Ki > 3(X)0 nM) for ai- and a2-adrenergic, histamine Hj, muscarinic, and DA D2 receptors, consistent with favorable side-effect profiles. Venlafaxine (1) and duloxetine (3) also have low affinity for a number of serotonergic receptors, and do not inhibit monoamine oxidase A or B. An expanded in vitro receptor profile of >50 receptors and binding sites... 

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