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1.
Am J Respir Cell Mol Biol ; 64(3): 331-343, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33264068

RESUMO

Monoamine oxidases (MAOs), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and cardiomyocytes contributes to vascular dysfunction and progression of left heart failure. We hypothesized that inhibition of MAO-A can be used to treat pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. MAO-A levels in lung and RV samples from patients with PAH were compared with levels in samples from donors without PAH. Experimental PAH was induced in male Sprague-Dawley rats by using Sugen 5416 and hypoxia (SuHx), and RV failure was induced in male Wistar rats by using pulmonary trunk banding (PTB). Animals were randomized to receive either saline or the MAO-A inhibitor clorgyline at 10 mg/kg. Echocardiography and RV catheterization were performed, and heart and lung tissues were collected for further analysis. We found increased MAO-A expression in the pulmonary vasculature of patients with PAH and in experimental experimental PAH induced by SuHx. Cardiac MAO-A expression and activity was increased in SuHx- and PTB-induced RV failure. Clorgyline treatment reduced RV afterload and pulmonary vascular remodeling in SuHx rats through reduced pulmonary vascular proliferation and oxidative stress. Moreover, clorgyline improved RV stiffness and relaxation and reversed RV hypertrophy in SuHx rats. In PTB rats, clorgyline had no direct clorgyline had no direct effect on the right ventricle effect. Our study reveals the role of MAO-A in the progression of PAH. Collectively, these findings indicated that MAO-A may be involved in pulmonary vascular remodeling and consecutive RV failure.


Assuntos
Progressão da Doença , Monoaminoxidase/metabolismo , Hipertensão Arterial Pulmonar/enzimologia , Animais , Clorgilina/farmacologia , Clorgilina/uso terapêutico , Modelos Animais de Doenças , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/enzimologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Direita/complicações , Hipertrofia Ventricular Direita/fisiopatologia , Indóis , Estresse Oxidativo/efeitos dos fármacos , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/enzimologia , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Pirróis , Ratos , Remodelação Vascular/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
2.
Eur J Med Chem ; 202: 112475, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32652406

RESUMO

A series of rasagiline-clorgyline hybrids was designed, synthesized and investigated in vitro for their inhibition of monoamine oxidase and amyloid-ß aggregation. Most of compounds were found to be selective and highly potent hMAO-B inhibitors showing IC50 values in the nanomolar, and exhibited a moderate inhibition of amyloid-ß aggregation. 7-((5-(methyl(prop-2-yn-1-yl)amino) pentyl)oxy)chroman-4-one (6j) was the most interesting compound identified in this research, endowed with higher hMAO-B potency (IC50 = 4 nM) and selectivity (SI > 25000) compared to the reference selective inhibitor rasagiline (IC50 = 141 nM, SI > 355), and exhibited good inhibitory activity against Aß1-42 aggregation (40.78%, 25 µM). Kinetic and molecular modeling studies revealed that 6j was a competitive reversible inhibitor for hMAO-B. Moreover, compound 6j displayed low toxicity and good neuroprotective effects in SH-SY5Y cell assay, and could penetrate the blood-brain barrier according to the parallel artificial membrane permeability assay. Pharmacokinetics assay revealed that compound 6j possessed good pharmacokinetic profiles after intravenous and oral administrations. Overall, these results highlighted that compound 6j was an effective and promising multitarget agent against Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clorgilina/química , Clorgilina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Indanos/química , Indanos/farmacologia , Masculino , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
3.
Nat Commun ; 11(1): 2689, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483206

RESUMO

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients. However, most patients eventually develop Enz resistance that may involve inducing the androgen receptor (AR) splicing variant 7 (ARv7). Here we report that high expression of monoamine oxidase-A (MAO-A) is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC.


Assuntos
Clorgilina/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Fenelzina/farmacologia , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Processamento Alternativo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Estabilidade Enzimática , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Nus , Camundongos SCID , Monoaminoxidase/química , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Células Neoplásicas Circulantes/metabolismo , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Clin Toxicol (Phila) ; 58(5): 383-387, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31373522

RESUMO

Context: Serotonin toxicity is a reported complication associated with both therapeutic use and overdose of metaxalone while on therapeutic doses of serotonergic drugs such as serotonin reuptake inhibitors. Monoamine oxidase A (MAO-A) inhibition by metaxalone has been proposed as the etiology of this toxicity. Metaxalone concentrations reported with cases of serotonin toxicity range from 31 to 61 mcg/ml (140-276 µM). We investigated the effect of metaxalone on MAO-A activity using an in vitro model.Methods: Metaxalone at concentrations ranging from 1.56 to 400 µM were incubated with a proprietary MAO substrate and recombinant human MAO-A for 1 h. After that, an esterase and luciferase were added and luminescence measured. Clorgyline, a known MAO-A inhibitor, was used as a positive control. Luminescence was measured using a Biotek Synergy HT microplate reader.Results: Metaxalone demonstrated significant dose-related inhibition of MAO-A activity. Four-parameter logistic regression analysis demonstrated a strong dose-response relationship at increasing concentrations.Conclusions: Our in vitro model shows that at toxic concentrations similar to those reported in case reports metaxalone shows significant MAO-A inhibition. Clinicians should be aware of this mechanism and understand the potentially lethal interactions metaxalone can have when prescribed with other serotonergic drugs and consider this as a potential cause of serotonin toxicity, especially in overdose scenarios.


Assuntos
Inibidores da Monoaminoxidase/toxicidade , Oxazolidinonas/toxicidade , Clorgilina/toxicidade , Relação Dose-Resposta a Droga , Humanos , Modelos Logísticos , Serotonina/toxicidade
5.
Neurochem Int ; 129: 104510, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31348967

RESUMO

The maladaptive form of aggressive behavior confers risk for violence and criminal incidences with profound impact on society. Although considerable research has been devoted to elucidate the etiology of aggression, molecular correlates of sex differences remains largely unexplored. Also, little attention has been given to whether males and females respond differently to similar causal factor of aggression. Here, we show the possible association of brain region specific neural activity (c-Fos expression) and monoamine oxidase A (MAOA) epigenetic state with sexual dimorphism in peripubertal stress (PPS) induced adulthood aggression. While PPS adult males exhibited escalated aggression, females spent maximal time in social exploration. c-Fos expression was brain region and sex specific. In the PPS adult cohort, only males showed elevated c-Fos expression in the prefrontal cortex, indicative of their hyper-responsive behavior. MAOA expression and enzyme activity was reduced in hypothalamus and increased in prefrontal cortex of hyper-aggressive male mice. Investigation into the underlying mechanisms revealed hypomethylation in prefrontal cortex and hypermethylation in hypothalamus of MAOA promoter negatively correlating with the expression pattern. On the other hand, binding of Sirt1 to MAOA promoter was diametrically opposite being increased in prefrontal cortex and reduced in hypothalamus. In females, neither expression nor epigenetic state of MAOA gene was significantly altered between control and PPS adult mice. Our study revealed novel epigenetic correlates of sexual dimorphism in stress induced aggressive psychopathology. However, given the multi-factorial nature with environmental influences, further studies are warranted to uncover the biological hub.


Assuntos
Hipotálamo/enzimologia , Monoaminoxidase/genética , Proteínas do Tecido Nervoso/genética , Córtex Pré-Frontal/enzimologia , Regiões Promotoras Genéticas , Caracteres Sexuais , Estresse Psicológico/genética , Agressão , Comportamento Agonístico , Animais , Sequência de Bases , Clorgilina/farmacologia , Metilação de DNA , Medo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Monoaminoxidase/análise , Inibidores da Monoaminoxidase/farmacologia , Proteínas do Tecido Nervoso/análise , Odorantes , Selegilina/farmacologia , Sirtuína 1/metabolismo
6.
Bioorg Med Chem Lett ; 29(9): 1090-1093, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30833108

RESUMO

Inhibition of MAO-B has been an effective strategy for the treatment of Parkinson's disease. To find more potent and selective MAO-B inhibitors with novel chemical scaffold, we designed and synthesized a series of new 2,3-dihydro-1H-inden-1-amine derivatives on basis of our previous study. Furthermore, the corresponding structure-activity relationship (SAR) of these compounds is detailedly discussed. Compounds L4 (IC50 = 0.11 µM), L8 (IC50 = 0.18 µM), L16 (IC50 = 0.27 µM) and L17 (IC50 = 0.48 µM) showed similar MAO-B inhibitory activity as Selegiline. Moreover, L4, L16 and L17 also exhibited comparable selectivity with Selegiline, indicating that L4, L16 and L17 could be promising selective MAO-B inhibitors for further study.


Assuntos
Antiparkinsonianos/síntese química , Antiparkinsonianos/farmacologia , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacologia , Antiparkinsonianos/química , Clorgilina/química , Clorgilina/farmacologia , Desenho de Fármacos , Humanos , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Conformação Proteica , Selegilina/química , Selegilina/farmacologia , Relação Estrutura-Atividade
8.
Prostate ; 79(6): 667-677, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30693539

RESUMO

BACKGROUND: Monoamine oxidase A (MAOA) is best known for its role in neuro-transmitter regulation. Monoamine oxidase inhibitors are used to treat atypical depression. MAOA is highly expressed in high grade prostate cancer and modulates tumorigenesis and progression in prostate cancer. Here, we investigated the potential role of MAOA inhibitors (MAOAIs) in relation to the androgen receptor (AR) pathway and resistance to antiandrogen treatment in prostate cancer. METHODS: We examined MAOA expression and the effect of MAOI treatment in relation to AR-targeted treatments using the LNCaP, C4-2B, and 22Rv1 human prostate cancer cell lines. MAOA, AR-full length (AR-FL), AR splice variant 7 (AR-V7), and PSA expression was evaluated in the presence of MAOAIs (clorgyline, phenelzine), androgenic ligand (R1881), and antiandrogen (enzalutamide) treatments. An enzalutamide resistance cell line was generated to test the effect of MAOAI treatment in this model. RESULTS: We observed that MAOAIs, particularly clorgyline and phenelzine, were effective at decreasing MAOA activity in human prostate cancer cells. MAOAIs significantly decreased growth of LNCaP, C4-2B, and 22Rv1 cells and produced additive growth inhibitory effects when combined with enzalutamide. Clorgyline decreased expression of AR-FL and AR-V7 in 22Rv1 cells and was effective at decreasing growth of an enzalutamide-resistant C4-2B cell line with increased AR-V7 expression. CONCLUSIONS: MAOAIs decrease growth and proliferation of androgen-sensitive and castration-resistant prostate cancer cells. Clorgyline, in particular, decreases expression of AR-FL and AR-V7 expression and decreases growth of an enzalutamide-resistant cell line. These findings provide preclinical validation of MAOA inhibitors either alone or in combination with antiandrogens for therapeutic intent in patients with advanced forms of prostate cancer.


Assuntos
Clorgilina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fenelzina/farmacologia , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Gradação de Tumores , Feniltioidantoína/farmacologia , Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia
9.
Langmuir ; 34(36): 10764-10773, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30049212

RESUMO

Monoamine oxidase A and B (MAO-A and B) are mitochondrial outer membrane enzymes that are implicated in a number of human diseases, and the pharmacological inhibition of these enzymes is a promising therapeutic strategy to alleviate disease symptoms. It has been suggested that optimal levels of enzymatic activity occur in the membrane-associated state, although details of the membrane association process remain to be understood. Herein, we have developed a supported lipid bilayer platform to study MAO-A and B binding and evaluate the effects of known pharmacological inhibitors on the membrane association process. By utilizing the quartz crystal microbalance-dissipation (QCM-D) technique, it was determined that both MAOs exhibit tight binding to negatively and positively charged bilayers with distinct concentration-dependent binding profiles while only transiently binding to neutral bilayers. Importantly, in the presence of known inhibitors, the MAOs showed increased binding to negatively charged bilayers, although there was no effect of inhibitor treatment on binding to positively charged bilayers. Taken together, our findings establish that the membrane association of MAOs is highly dependent on membrane surface charge, and we outline an experimental platform to support the in vitro reconstitution of monoamine oxidases on synthetic membranes, including the evaluation of pharmacological drug candidates.


Assuntos
Bicamadas Lipídicas/metabolismo , Monoaminoxidase/metabolismo , Clorgilina/química , Indanos/química , Bicamadas Lipídicas/química , Inibidores da Monoaminoxidase/química , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Fosfatidilserinas/química , Fosfatidilserinas/metabolismo , Ligação Proteica , Técnicas de Microbalança de Cristal de Quartzo , Eletricidade Estática
10.
Bioorg Med Chem Lett ; 28(4): 584-588, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29395970

RESUMO

Hispidol, an aurone, isolated from Glycine max Merrill, was found to potently and selectively inhibit an isoform of recombinant human monoamine oxidase-A (MAO-A), with an IC50 value of 0.26 µM, and to inhibit MAO-B, but with lower potency (IC50 = 2.45 µM). Hispidol reversibly and competitively inhibited MAO-A with a Ki value of 0.10 µM with a potency much greater than toloxatone (IC50 = 1.10 µM), a marketed drug. It also reversibly and competitively inhibited MAO-B (Ki = 0.51 µM). Sulfuretin, an analog of hispidol, effectively inhibited MAO-A (IC50 = 4.16 µM) but not MAO-B (IC50 > 80 µM). A comparison of their chemical structures showed that the 3'-hydroxyl group of sulfuretin might reduce its inhibitory activities against MAO-A and MAO-B. Flexible docking simulation revealed that the binding affinity of hispidol for MAO-A (-9.1 kcal/mol) was greater than its affinity for MAO-B (-8.7 kcal/mol). The docking simulation showed hispidol binds to the major pocket of MAO-A or MAO-B. The findings suggest hispidol is a potent, selective, reversible inhibitor of MAO-A, and that it be considered a novel lead compound for development of novel reversible inhibitors of MAO-A.


Assuntos
Benzofuranos/química , Inibidores da Monoaminoxidase/química , Sítios de Ligação , Clorgilina/química , Flavonoides/química , Humanos , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Monoaminoxidase/química , Oxazolidinonas/química , Ácidos Picolínicos/química
11.
J Med Chem ; 60(16): 7206-7212, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28753307

RESUMO

Because of the lack of significant disease-modifying drugs for neurodegenerative disorders, a pressing need for new chemical entities endowed with IMAO-B still exists. Within this framework, and for the first time, a study was performed to compare coumarin- and chomone-3-phenylcarboxamide scaffolds. Compounds 10a and 10b were the most potent, selective, and reversible noncompetitive IMAO-B. The benzopyrone sp2 oxygen atom was found to be position independent and a productive contributor for the ligand-enzyme complex stability.


Assuntos
Cromonas/farmacologia , Cumarínicos/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Alanina/análogos & derivados , Alanina/farmacologia , Benzilaminas/farmacologia , Cromonas/síntese química , Cromonas/química , Clorgilina/farmacologia , Cumarínicos/síntese química , Cumarínicos/química , Humanos , Indanos/farmacologia , Cinética , Ligantes , Simulação de Acoplamento Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Selegilina/farmacologia , Relação Estrutura-Atividade
12.
J Pathol ; 243(2): 220-229, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28722111

RESUMO

Monoamine oxidase A (MAOA) is a mitochondrial enzyme that catalyzes oxidative deamination of neurotransmitters and dietary amines and produces H2 O2 . It facilitates the progression of gliomas and prostate cancer, but its expression and functional relevance have not been studied in lymphoma. Here, we evaluated MAOA in 427 cases of Hodgkin and non-Hodgkin lymphoma and in a spectrum of reactive lymphoid tissues by immunohistochemistry on formalin-fixed, paraffin-embedded specimens. MAOA was expressed by Hodgkin Reed-Sternberg (HRS) cells in the majority of classical Hodgkin lymphomas (cHLs) (181/241; 75%), with 34.8% showing strong expression. Weak MAOA was also noted in a minority of primary mediastinal large B-cell lymphomas (8/47; 17%) and in a mediastinal gray-zone lymphoma. In contrast, no MAOA was found in non-neoplastic lymphoid tissues, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL; 0/8) or any other non-Hodgkin lymphomas studied (0/123). MAOA was more common in Epstein-Barr virus (EBV)-negative compared to EBV-positive cHL (p < 0.0001) and was especially prevalent in the EBV-negative nodular sclerosing subtype. Similar to primary human lymphoma specimens, most cHL-derived cell lines displayed MAOA activity, whereas non-Hodgkin-lymphoma-derived cell lines did not. The MAOA inhibitor clorgyline reduced the growth of L1236 cells and U-HO1 cells, and shRNA knockdown of MAOA reduced the growth of L1236 cells. Conversely, ectopic overexpression of MAOA increased the growth of MAOA-negative HDLM2 cells. Combined treatment with clorgyline and ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) was more effective in reducing cell growth than either regimen alone. In summary, MAOA is highly expressed in cHL and may reflect the distinct biology of this lymphoma. Further studies on the potential utility of MAOA as a diagnostic marker and therapeutic target are warranted. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Doença de Hodgkin/enzimologia , Monoaminoxidase/metabolismo , Linhagem Celular Tumoral , Clorgilina/farmacologia , Infecções por Vírus Epstein-Barr/enzimologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Monoaminoxidase/farmacologia , Células de Reed-Sternberg/metabolismo
13.
ACS Chem Neurosci ; 8(5): 1026-1035, 2017 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27977122

RESUMO

The regulation of brain monoamine levels is paramount for cognitive functions, and the monoamine oxidase (MAO A and B) enzymes play a central role in these processes. The aim of this study was to evaluate whether the procognitive properties exerted by propargylamine N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine (F2MPA) are related to changes in monoamine content via MAO inhibition. In vivo microdialysis and ex vivo amine metabolite measurement demonstrated region-specific alterations in monoamine metabolism that differ from both of the classic MAO A and MAO B inhibitors, clorgyline and l-deprenyl, respectively. Although all the inhibitors (1 and 4 mg/kg) increased cortical serotonin tissue content, only F2MPA increased the levels of cortical noradrenaline. In the striatum, clorgyline (1 mg/kg), but not F2MPA (1 mg/kg), reduced extracellular levels of dopamine metabolites at rest or stimulated by the intrastriatal application of the MAO substrate 3-methoxytyramine. In vitro, F2MPA exhibited a low affinity toward MAO B and MAO A. Nonetheless, it modified the B form of MAO, forming a flavin adduct structurally similar to that with deprenyl. F2MPA was rapidly metabolized in the presence of rat but not human microsomes, producing a hydroxylated derivative. In conclusion, the effect of F2MPA on cognition may arise from monoaminergic changes in the cortex, but the role of MAO in this process is likely to be negligible, consistent with the poor affinity of F2MPA for MAO.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Furanos/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Norepinefrina/metabolismo , Serotonina/metabolismo , Animais , Córtex Cerebral/metabolismo , Clorgilina/farmacologia , Masculino , Microdiálise , Ratos , Ratos Sprague-Dawley , Selegilina/farmacologia
14.
PLoS One ; 11(11): e0166750, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27861613

RESUMO

3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a commonly abused recreational drug that causes neurotoxic effects in both humans and animals. The mechanism behind MDMA-induced neurotoxicity is suggested to be species-dependent and needs to be further investigated on the cellular level. In this study, the effects of MDMA in neuronally differentiated P19 mouse embryonal carcinoma cells have been examined. MDMA produces a concentration-, time- and temperature-dependent toxicity in differentiated P19 neurons, as measured by intracellular MTT reduction and extracellular LDH activity assays. The P19-derived neurons express both the serotonin reuptake transporter (SERT), that is functionally active, and the serotonin metabolizing enzyme monoamine oxidase A (MAO-A). The involvement of these proteins in the MDMA-induced toxicity was investigated by a pharmacological approach. The MAO inhibitors clorgyline and deprenyl, and the SERT inhibitor fluoxetine, per se or in combination, were not able to mimic the toxic effects of MDMA in the P19-derived neurons or block the MDMA-induced cell toxicity. Oxidative stress has been implicated in MDMA-induced neurotoxicity, but pre-treatment with the antioxidants α-tocopherol or N-acetylcysteine did not reveal any protective effects in the P19 neurons. Involvement of mitochondria in the MDMA-induced cytotoxicity was also examined, but MDMA did not alter the mitochondrial membrane potential (ΔΨm) in the P19 neurons. We conclude that MDMA produce a concentration-, time- and temperature-dependent neurotoxicity and our results suggest that the mechanism behind MDMA-induced toxicity in mouse-derived neurons do not involve the serotonergic system, oxidative stress or mitochondrial dysfunction.


Assuntos
N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clorgilina/farmacologia , Células-Tronco de Carcinoma Embrionário , Fluoxetina/farmacologia , Expressão Gênica , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Selegilina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
15.
Psychopharmacology (Berl) ; 233(15-16): 2955-71, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27259485

RESUMO

RATIONALE: Fas-associated death domain (FADD) is an adaptor of death receptors that can also induce anti-apoptotic actions through its phosphorylated form (p-FADD). Activation of monoamine receptors, indirect targets of classic anti-depressant drugs (ADs), reduced FADD and increased p-FADD and p-FADD/FADD ratio in brain. OBJECTIVES: To ascertain whether ADs, which indirectly regulate monoamine receptors, modulate FADD protein forms to promote anti-apoptotic actions. METHODS: The effects of selected norepinephrine transporter (NET), serotonin transporter (SERT), monoamine oxidase (MAO) inhibitors, atypical ADs, and electroconvulsive shock (ECS) or behavioral procedures (forced swim test, FST) on FADD forms and pro-survival FADD-like interleukin-1ß-converting enzyme-inhibitory protein (FLIP-L) and phosphoprotein enriched in astrocytes of 15 kDa (p-PEA-15) contents were assessed in rat brain cortex by western blot analysis. RESULTS: Acute NET (e.g., nisoxetine) but not SERT (e.g., fluoxetine) inhibitors decreased cortical FADD (up to 37 %) and increased p-FADD/FADD ratio (up to 1.9-fold). Nisoxetine effects were prevented by α2-antagonist RX-821002, suggesting the involvement of presynaptic α2-autoreceptors. Immobility time in the FST correlated with increases of pro-apoptotic FADD and decreases of anti-apoptotic p-FADD. The MAO-A/B inhibitor phenelzine decreased FADD (up to 33 %) and increased p-FADD (up to 65 %) and p-FADD/FADD (up to 2.4-fold). Other MAO inhibitors (clorgyline, Ro 41-1049, rasagiline), atypical ADs (ketamine and mirtazapine), or ECS did not modulate cortical FADD. Chronic (14 days) desipramine and fluoxetine, but not phenelzine, increased p-FADD (up to 59 %), p-FADD/FADD ratio (up to 1.8-fold), and pro-survival p-PEA-15 (up to 46 %) in rat brain cortex. CONCLUSIONS: Multifunctional FADD protein, through an increased p-FADD/FADD ratio, could participate in the mechanisms of anti-apoptotic actions induced by ADs.


Assuntos
Antidepressivos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Desipramina/farmacologia , Proteína de Domínio de Morte Associada a Fas/efeitos dos fármacos , Fluoxetina/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Apoptose , Autorreceptores/metabolismo , Western Blotting , Encéfalo/efeitos dos fármacos , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD , Córtex Cerebral/metabolismo , Clorgilina/farmacologia , Eletrochoque , Antagonistas de Aminoácidos Excitatórios/farmacologia , Proteína de Domínio de Morte Associada a Fas/metabolismo , Fluoxetina/análogos & derivados , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Indanos/farmacologia , Ketamina/farmacologia , Masculino , Mianserina/análogos & derivados , Mianserina/farmacologia , Mirtazapina , Inibidores da Monoaminoxidase/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Fenelzina/farmacologia , Fosfoproteínas/efeitos dos fármacos , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas de Ligação a RNA/antagonistas & inibidores , Ratos , Tiazóis/farmacologia
16.
ChemMedChem ; 11(14): 1551-67, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27332045

RESUMO

A series of 2-amino-6-nitrobenzothiazole-derived extended hydrazones were designed, synthesized, and investigated for their ability to inhibit monoamine oxidase A and B (MAO-A/MAO-B). The compounds were found to exhibit inhibitory activities in the nanomolar to micromolar range. Some of the compounds showed excellent potency and selectivity against the MAO-B isoform. N'-(5-Chloro-2-oxoindolin-3-ylidene)-2-(6-nitrobenzothiazol-2-ylamino)acetohydrazide (compound 31) showed the highest MAO-B inhibitory activity (IC50 =1.8±0.3 nm, selectivity index [SI]=766.67), whereas compound 6 [N'-(1-(4-bromophenyl)ethylidene)-2-(6-nitrobenzothiazol-2-ylamino)acetohydrazide] was found to be the most active MAO-A inhibitor (IC50 =0.42±0.003 µm). Kinetic studies revealed that compounds 6 and 31 exhibit competitive-type reversible inhibition against both MAO-A and MAO-B, respectively. Structure-activity relationship (SAR) studies disclosed several structural aspects significant for potency and the contribution of the methylene spacer toward MAO-B inhibitory potency, with minimal or no neurotoxicity. Molecular modeling studies yielded a good correlation between experimental and theoretical inhibitory data. Binding pose analysis revealed the significance of cumulative effects of π-π stacking and hydrogen bond interactions for effective stabilization of virtual ligand-protein complexes. Further optimization studies of compound 31, including co-crystallization of inhibitor-MAO-B complexes, are essential to develop these compounds as potential therapeutic agents for MAO-B-associated neurodegenerative diseases.


Assuntos
Benzotiazóis/farmacologia , Hidrazonas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/farmacologia , Antidepressivos/toxicidade , Benzotiazóis/síntese química , Benzotiazóis/química , Benzotiazóis/toxicidade , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Domínio Catalítico , Clorgilina/farmacologia , Desenho de Fármacos , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/toxicidade , Ligação de Hidrogênio , Cinética , Ligantes , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/toxicidade , Fenitoína/toxicidade , Ratos , Selegilina/farmacologia , Relação Estrutura-Atividade
17.
Exp Neurol ; 278: 4-10, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26825854

RESUMO

Abnormal monoamine oxidase A and B (MAO-A/B) activity and an imbalance in monoamine neurotransmitters have been suggested to underlie the pathobiology of depression, a major psychiatric symptom observed in patients with neurodegenerative diseases, such as Huntington disease (HD). Increased MAO-A/B activity has been observed in brain tissue from patients with HD and in human and rodent HD neural cells. Using the YAC128 mouse model of HD, we studied the effect of an irreversible MAO-A inhibitor, clorgyline, on the levels of select monoamine neurotransmitters associated with affective function. We observed a decrease in striatal levels of the MAO-A/B substrates, dopamine and norepinephrine, in YAC128 HD mice compared with wild-type mice, which was accompanied by increased anxiety- and depressive-like behaviour at five months of age. Treatment for 26 days with clorgyline restored dopamine, serotonin, and norepinephrine neurotransmitter levels in the striatum and reduced anxiety- and depressive-like behaviour in YAC128 HD mice. This study supports a potential therapeutic use for MAO-A inhibitors in the treatment of depression and anxiety in patients with HD.


Assuntos
Clorgilina/uso terapêutico , Modelos Animais de Doenças , Doença de Huntington/complicações , Inibidores da Monoaminoxidase/uso terapêutico , Transtornos do Humor , Neurotransmissores/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Elevação dos Membros Posteriores , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Monoaminoxidase/metabolismo , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/etiologia , Transtornos do Humor/metabolismo , Mutação/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Natação
18.
Bioorg Med Chem Lett ; 25(22): 5281-5, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26428872

RESUMO

The 3-substituted oxindole derivatives were designed, synthesized, and evaluated for antidepressant activity by employing forced swimming test, tail suspension test, and MAO-A inhibition assay. Results of biological studies revealed that the majority of compounds exhibited potent to moderately potent activity and among them, 12 displayed potency comparable to that of the imipramine with %DID of 37.95 and 44.84 in the FST and TST, respectively. At the same time, imipramine showed %DID of 43.62 and 50.64 in the FST and TST, correspondingly. In the MAO-A inhibition assay, 12 showed an IC50 of 18.27 µmol, whereas the reference drug moclobemide displayed an IC50 of 13.1 µmol. The SAR study disclosed that the presence of bromo atom at the phenyl/furanyl or thienyl moiety in the oxindole derivatives was critical for the antidepressant activity.


Assuntos
Antidepressivos/química , Compostos de Benzilideno/química , Indóis/química , Lactamas/química , Inibidores da Monoaminoxidase/química , Animais , Antidepressivos/síntese química , Antidepressivos/farmacologia , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/farmacologia , Clorgilina/farmacologia , Imipramina/farmacologia , Indóis/síntese química , Indóis/farmacologia , Lactamas/síntese química , Lactamas/farmacologia , Camundongos , Moclobemida/farmacologia , Simulação de Acoplamento Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacologia , Relação Estrutura-Atividade
19.
Molecules ; 20(9): 15976-88, 2015 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-26364629

RESUMO

Three series of 4,6-dimethoxy-, 4,6-dipiperidino- and 4,6-dimorpholino-1,3,5-triazin-2-yl) amino acid derivatives were synthesized and characterized. A preliminary study for their monoamine oxidase inhibitory activity showed that compounds 7, 18, and 25 had MAO-A inhibition activity comparable to that of the standard clorgyline, with apparently more selective inhibitory activity toward MAO-A than MAO-B and no significant acute toxicity.


Assuntos
Aminoácidos/química , Inibidores da Monoaminoxidase/síntese química , Triazinas/química , Clorgilina/farmacologia , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Morfolinas/química , Piperidinas/química , Relação Quantitativa Estrutura-Atividade
20.
Can J Physiol Pharmacol ; 93(9): 819-25, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26322912

RESUMO

Monoamine oxidases (MAOs) have recently emerged as important mitochondrial sources of oxidative stress in the cardiovascular system. Generation of reactive oxygen species during the brief episodes of ischemic preconditioning (IPC) is responsible for the cardioprotection at reperfusion. The aim of this study was to assess the effects of two MAO inhibitors (clorgyline and pargyline) on the IPC-related protection in isolated rat hearts. Animals subjected to 30 min global ischemia and 120 min reperfusion were assigned to the following groups: (i) Control, no additional intervention; (ii) IPC, 3 cycles of 5 min ischemia and 5 min reperfusion before the index ischemia; (iii) IPC-clorgyline, IPC protocol bracketed for 5 min with clorgyline (50 µmol/L); (iv) IPC-pargyline, IPC protocol bracketed for 5 min with pargyline (0.5 mmol/L). The postischemic functional recovery was assessed by the left ventricular developed pressure (LVDP) and the indices of contractility (+dLVP/dt max) and relaxation (-dLVP/dt max). Infarct size (IS) was quantified by TTC staining. In both genders, IPC significantly improved functional recovery that was further enhanced in the presence of either clorgyline or pargyline. IS reduction was comparable among all the preconditioned groups, regardless of the presence of MAO inhibitors. In isolated rat hearts, acute inhibition of MAOs potentiates the IPC-induced postischemic functional recovery without interfering with the anti-necrotic protection.


Assuntos
Clorgilina/farmacologia , Precondicionamento Isquêmico Miocárdico , Inibidores da Monoaminoxidase/farmacologia , Infarto do Miocárdio/patologia , Pargilina/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Feminino , Masculino , Infarto do Miocárdio/enzimologia , Ratos
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