The new generation of monoamine oxidase inhibitors

Cesura, Andrea M.; Pletscher, A.

doi:10.1007/978-3-0348-7141-9_3

Cited by 137 publications

(142 citation statements)

References 520 publications

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“…In mammals, MAO is present as two isoforms (MAO A and MAO B), which are separate gene products, that exhibit over 70% sequence identity and distinct but overlapping substrate specificities in the catabolism of neurotransmitters, such as dopamine and serotonin (11,12). Both MAO A and MAO B are implicated in a large number of neurological disorders and are a target for drugs against Parkinson's disease and depression (13). Mammalian MAOs are bound to the outer mitochondrial membrane and have a FAD molecule covalently bound to the protein via an 8␣-thioether linkage to a cysteinyl residue (14).…”

Section: From the ‡Department Of Genetics And Microbiology Universitmentioning

confidence: 99%

Structure-Function Relationships in Flavoenzyme-dependent Amine Oxidations

Binda¹,

Mattevi²,

Edmondson³

2002

Journal of Biological Chemistry

160

132

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Amine oxidations are important in a number of basic biological processes ranging from lysyl oxidation in the cross-linking of collagen to the degradative metabolism of polyamines and neurotransmitters. The oxidations of biogenic amines to the corresponding imines are catalyzed by either the quinoprotein class of enzymes (usually primary amines) (1) or by the flavin-containing amine oxidases (primary, secondary, or tertiary amines) (2). In both cases, molecular oxygen is the usual electron acceptor with hydrogen peroxide formed as reaction product. Flavin amine oxidases (2) catalyze the oxidation of amines via an oxidative cleavage of the ␣-CH bond of the substrate to form an imine product with the concomitant reduction of the flavin cofactor (Fig. 1A). The imine product is then hydrolyzed (non-enzymatically in the cases investigated) to the corresponding aldehyde and ammonia (or amine for secondary or tertiary amine substrates). The reduced flavin coenzyme reacts with oxygen to form hydrogen peroxide and the oxidized form of the flavin to complete the catalytic cycle.The focus of this minireview is the structure and function of plant polyamine oxidase (PAO) 1 and human monoamine oxidase (MAO), two thoroughly investigated members of the flavin-dependent class of amine oxidases. Both enzymes have been structurally characterized by x-ray crystallography (3, 4). Plant PAO is involved in the catabolism of polyamines (Fig. 1B) by catalyzing the oxidation of the secondary amino groups of spermine or spermidine and their acetyl derivatives (5). It is a soluble enzyme with a noncovalently bound FAD cofactor (6, 7). Very recently, the gene for human PAO has been identified (8), and the protein was investigated in preliminary work. Polyamines are essential for cell growth and differentiation (9), and their metabolism is the subject of extensive research to develop potential targets for antiproliferative drugs (10).MAOs oxidize the primary amino groups of arylalkyl amines (Fig. 1C) and are widely distributed in higher eukaryotes. In mammals, MAO is present as two isoforms (MAO A and MAO B), which are separate gene products, that exhibit over 70% sequence identity and distinct but overlapping substrate specificities in the catabolism of neurotransmitters, such as dopamine and serotonin (11,12). Both MAO A and MAO B are implicated in a large number of neurological disorders and are a target for drugs against Parkinson's disease and depression (13). Mammalian MAOs are bound to the outer mitochondrial membrane and have a FAD molecule covalently bound to the protein via an 8␣-thioether linkage to a cysteinyl residue (14). They are expressed in both a tissue-dependent and an age-dependent manner and have been the subject of extensive clinical and pharmacological studies with more than 15,000 papers currently listed in the Medline index. A good deal of mechanistic information is available for these two isozymes (see below). Crystal Structures of PAO and MAOThe recent determination of the crystal structures of plant PAO and human M...

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Section: From the ‡Department Of Genetics And Microbiology Universitmentioning

confidence: 99%

Structure-Function Relationships in Flavoenzyme-dependent Amine Oxidations

Binda¹,

Mattevi²,

Edmondson³

2002

Journal of Biological Chemistry

160

132

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“…According to biochemical and pharmacologic properties, this enzyme exists in A and B isoforms (5). In the human brain, MAO-B is the predominant isoform and constitutes up to about 70% of total brain MAO activity (6). MAO-B selectively oxidizes monoamines such as O-tyramine, phenethylamine, and tele-N-methyl histamine and generates hydrogen peroxide, which can react to form highly reactive oxygen species (7).…”

mentioning

confidence: 99%

In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand, ¹⁸F-Labeled Deuterated Fluorodeprenyl

et al. 2015

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The aim of this study was to radiolabel a novel bis-deuterium substituted L-deprenyl analog (fluorodeprenyl-D 2 ) with 18 F and to evaluate its potential to visualize and quantify monoamine oxidase (MAO) B activity in vivo. Methods: The precursor compound (5a 1 5b) and reference standard (6) were synthesized in multistep syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used to determine inhibitory concentrations of 50%. Radiolabeling was accomplished by a nucleophilic substitution reaction. Whole-hemisphere autoradiography was performed with 18 F-fluorodeprenyl-D 2 . A PET study was performed on a cynomolgus monkey. Radiometabolites were measured in monkey plasma using high-performance liquid chromatography. Results: The 50% inhibitory concentration of compound 6 for MAO-B was 227 ± 36.8 nM. Radiolabeling was accomplished with high radiochemical yield, purity, and specific radioactivity. The autoradiography binding density of 18 F-fluorodeprenyl-D 2 was consistent with known MAO-B expression in the human brain. In vivo, 18 F-fluorodeprenyl-D 2 showed favorable kinetic properties, with relatively fast washout from the brain. Regional time-activity curves were better described by the 2-tissuecompartment model. Administration of a 1 mg/kg dose of L-deprenyl yielded 70% inhibition of MAO-B in all regions. Radiometabolite studies demonstrated 20% unchanged radioligand at 120 min after injection. 18 F-fluorodeprenyl-D 2 showed less irreversibility than did previously reported MAO-B radioligands. Conclusion: The results suggest that 18 F-fluorodeprenyl-D 2 is a suitable PET radioligand for visualization of MAO-B activity in the human brain.

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“…Neste contexto, insere-se a segunda geração de inibidores de MAO, representados pela clorgilina (5), inibidor seletivo para a isoforma A (IMAO A), e selegilina (6), inibidor seletivo para a isoenzima B (IMAO B), os quais, embora seletivos, ligam-se irreversivelmente às enzimas 14 . Em seguida, novos inibidores de curta duração de ação, como a meclobemida (7) e RO-19-6327 (8), compuseram a terceira geração de inibidores, reversíveis e seletivos (IRMA e IRMB) 15 . Uma vez que a MAO-B, no cérebro, tem preferência por DA como substrato, seus inibidores seletivos têm sido úteis na terapia da deficiência dopaminérgica associada à doença de Parkinson (Figura 2) 16 .…”

Section: Terapia Eletroconvulsiva (Tec)unclassified

Novas estratégias terapêuticas para o tratamento da depressão: uma visão da química medicinal

2003

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Depression is a widespread humor disturbance promoted mainly by depletion of biogenic neurotransmitter amines involved in the CNS synapses. Effective drug treatments for depression have been available for more than forty years. Despite its remarkable structural diversity, this paper discuss under the medicinal chemistry point of view, all different classes of "monoamine based" antidepressant drugs, emphasizing the rational design, structure-activity relationships (SAR), biotransformation and physicochemical properties related with antidepressant activity and molecular mechanism of action.Keywords: monoamine oxidase inhibitors; monoamine reuptake inhibitors; serotonin receptor antagonists. INTRODUÇÃOOs distúrbios do humor são graves perturbações do estado emocional, que devem ser distinguidos das alterações do afeto, i.e. manifestações externas de um estado emocional interno 1 . Depressão e mania são freqüentemente considerados como pontos extremos da alteração do humor ou afetiva. Classicamente, estes distintos pólos da variação do humor originaram os termos unipolar, para o estado depressivo, no qual pacientes evidenciam acentuada diminuição do estado normal de humor, e distúrbio bipolar, em que os pacientes alternam, em diferentes momentos, quadros de diminuição (depressão) e exacerbação (mania) de humor. Na prática, a depressão e a mania podem ocorrer simultaneamente, caracterizando um estado afetivo misto 2 . A depressão consiste em um sentimento que é universalmente experimentado por todos os seres humanos no decorrer de suas vidas. A distinção entre o sentimento depressivo normal e o quadro patológico, que necessita de tratamento médico, é extremamente problemática para pessoas não especializadas em saúde mental. Neste contexto, estigmas e desinformação levaram à crença de que a depressão não seria doença, mas consistiria numa deficiência de cará-ter, a qual poderia ser superada com esforço pelo indivíduo. Os critérios de diagnóstico dos distúrbios de humor estão em constante evolução, com atualizações nosológicas agrupadas no Manual de Diagnóstico e Estatística dos Distúrbios Mentais (DMS-IV) 3 . A qualidade do humor, seu grau de desvio da normalidade e sua duração são características chave de um distúrbio afetivo. Contudo, em adição, os clínicos devem avaliar outros sintomas, na formulação de um diagnóstico mais preciso, como as características vegetativas, e.g. sono, apetite, peso e libido; cognitivas, e.g. atenção, tolerância à frustração, memória; comportamentais, e.g. motivação, prazer, interesse, fadiga; físicas ou somáticas, e.g. cefaléia, dores estomacais e tensão muscular e controle do impulso, e.g. suicídio e homicídio. Dados da Organização Mundial de Saúde (OMS) indicam que13-20% da população mundial apresentam sintomas depressivos, sendo 2-3% desse total atribuídos a indivíduos com transtornos afetivos graves, dos quais 15-30% cometem suicídio ou são potenciais suicidas. Mesmo sob tratamento médico, 30% dos pacientes com diagnóstico depressivo não respondem à terapia farmacológica, devido ao t...

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The new generation of monoamine oxidase inhibitors

Cited by 137 publications

References 520 publications

Structure-Function Relationships in Flavoenzyme-dependent Amine Oxidations

Structure-Function Relationships in Flavoenzyme-dependent Amine Oxidations

In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand, ¹⁸F-Labeled Deuterated Fluorodeprenyl

Novas estratégias terapêuticas para o tratamento da depressão: uma visão da química medicinal

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The new generation of monoamine oxidase inhibitors

Cited by 137 publications

References 520 publications

Structure-Function Relationships in Flavoenzyme-dependent Amine Oxidations

Structure-Function Relationships in Flavoenzyme-dependent Amine Oxidations

In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand, 18F-Labeled Deuterated Fluorodeprenyl

Novas estratégias terapêuticas para o tratamento da depressão: uma visão da química medicinal

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In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand, ¹⁸F-Labeled Deuterated Fluorodeprenyl