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1.
Postepy Biochem ; 67(2): 130-140, 2021 06 30.
Artigo em Polonês | MEDLINE | ID: mdl-34378889

RESUMO

The aim of this article is to synthesize informations about monoamine oxidase inhibitors drugs (MAOI) used in the treatment of depression. General informations on monoamine oxidase (MAO) and its kinetic properties are presented. MAO is an enzyme that degrades catecholamines and their 3-methoxy derivatives and other monoamines, for example serotonin or tryptamine. The criteria and symptoms of depressive disorders are discussed. They have to be distinguished from the state of sadness and similar states. The basic symptoms include: voice, facial expressions, anhedonia and psychomotor slowness. They may differ in individual diagnostic units. The following basic mechanism of the pharmacological action of MAOI has been indicated: when a drug inhibits MAO, the degradation of monoamines decreases and the concentration of the neurotransmitter in the synaptic cleft increases. Informations on selected selective and reversible MAOI-A are presented in the following sections. These are currently the safest and most effective MAOI drugs that can be used in the treatment of depressive diseases. The following drugs are discussed: moclobemide, befloxatone, toloxatone and brofaromine. Final conclusions are given and the presented data summarized.


Assuntos
Depressão , Inibidores da Monoaminoxidase , Depressão/tratamento farmacológico , Humanos , Moclobemida , Monoaminoxidase , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico
2.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445126

RESUMO

Experimental and clinical studies have suggested that several neurological disorders are associated with the occurrence of central nervous system neuroinflammation. Metaxalone is an FDA-approved muscle relaxant that has been reported to inhibit monoamine oxidase A (MAO-A). The aim of this study was to investigate whether metaxalone might exert antioxidant and anti-inflammatory effects in HMC3 microglial cells. An inflammatory phenotype was induced in HMC3 microglial cells through stimulation with interleukin-1ß (IL-1ß). Control cells and IL-1ß-stimulated cells were subsequently treated with metaxalone (10, 20, and 40 µM) for six hours. IL-1ß stimulated the release of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), but reduced the anti-inflammatory cytokine interleukin-13 (IL-13). The upstream signal consisted of an increased priming of nuclear factor-kB (NF-kB), blunted peroxisome proliferator-activated receptor gamma (PPARγ), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression. IL-1ß also augmented MAO-A expression/activity and malondialdehyde levels and decreased Nrf2 mRNA expression and protein levels. Metaxalone decreased MAO-A activity and expression, reduced NF-kB, TNF-α, and IL-6, enhanced IL-13, and also increased PPARγ, PGC-1α, and Nrf2 expression. The present experimental study suggests that metaxalone has potential for the treatment of several neurological disorders associated with neuroinflammation.


Assuntos
Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Microglia/efeitos dos fármacos , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Oxazolidinonas/farmacologia , Anti-Inflamatórios , Linhagem Celular , Humanos , Inflamação/metabolismo , Interleucina-13/metabolismo , Interleucina-6/metabolismo , Microglia/metabolismo , PPAR gama/metabolismo , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
3.
Biomolecules ; 11(7)2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34356625

RESUMO

Monoamine oxidases (MAOs) and muscarinic acetylcholine receptors (mAChRs) are considered important therapeutic targets for Parkinson's disease (PD). Lipophilic tanshinones are major phytoconstituents in the dried roots of Salvia miltiorrhiza that have demonstrated neuroprotective effects against dopaminergic neurotoxins and the inhibition of MAO-A. Since MAO-B inhibition is considered an effective therapeutic strategy for PD, we tested the inhibitory activities of three abundant tanshinone congeners against recombinant human MAO (hMAO) isoenzymes through in vitro experiments. In our study, tanshinone I (1) exhibited the highest potency against hMAO-A, followed by tanshinone IIA and cryptotanshinone, with an IC50 less than 10 µM. They also suppressed hMAO-B activity, with an IC50 below 25 µM. Although tanshinones are known to inhibit hMAO-A, their enzyme inhibition mechanism and binding sites have yet to be investigated. Enzyme kinetics and molecular docking studies have revealed the mode of inhibition and interactions of tanshinones during enzyme inhibition. Proteochemometric modeling predicted mAChRs as possible pharmacological targets of 1, and in vitro functional assays confirmed the selective M4 antagonist nature of 1 (56.1% ± 2.40% inhibition of control agonist response at 100 µM). These findings indicate that 1 is a potential therapeutic molecule for managing the motor dysfunction and depression associated with PD.


Assuntos
Abietanos , Inibidores da Monoaminoxidase , Monoaminoxidase , Fenantrenos , Receptor Muscarínico M4 , Salvia miltiorrhiza/química , Abietanos/química , Abietanos/farmacologia , Animais , Células CHO , Cricetulus , Humanos , Monoaminoxidase/química , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Fenantrenos/química , Fenantrenos/farmacologia , Receptor Muscarínico M4/antagonistas & inibidores , Receptor Muscarínico M4/química , Receptor Muscarínico M4/genética , Receptor Muscarínico M4/metabolismo
4.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361702

RESUMO

Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin-coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11-18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H2O2 in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtained.


Assuntos
Antioxidantes/síntese química , Inibidores da Colinesterase/síntese química , Cumarínicos/síntese química , Curcumina/análogos & derivados , Inibidores da Monoaminoxidase/síntese química , Fármacos Neuroprotetores/síntese química , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Cumarínicos/farmacologia , Curcumina/farmacologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Córtex Motor/citologia , Córtex Motor/enzimologia , Nanopartículas/química , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Fármacos Neuroprotetores/farmacologia , Picratos/antagonistas & inibidores , Cultura Primária de Células , Ratos , Relação Estrutura-Atividade
5.
J Enzyme Inhib Med Chem ; 36(1): 1607-1621, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34281458

RESUMO

Multitarget directed ligands (MTDLs) are emerging as promising treatment options for Alzheimer's disease (AD). Coumarin derivatives serve as a good starting point for designing MTDLs due to their inherent inhibition of monoamine oxidase (MAO) and cholinesterase enzymes, which are complicit in AD's complex pathophysiology. A preliminary series of 3,7-substituted coumarin derivatives were synthesised and evaluated for enzyme inhibitory activity, cytotoxicity as well as neuroprotective ability. The results indicated that the compounds are weak cholinesterase inhibitors with five compounds demonstrating relatively potent inhibition and selectivity towards MAO-B with IC50 values between 0.014 and 0.498 hx00B5;µM. Significant neuroprotective effects towards MPP+-compromised SH-SY5Y neuroblastoma cells were also observed, with no inherent cytotoxicity at 10 µM for all compounds. The overall results demonstrated that substitution of the phenylethyloxy moiety at the 7-position imparted superior general activity to the derivatives, with the propargylamine substitution at the 3-position, in particular, displaying the best MAO-B selectivity and neuroprotection.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cumarínicos/farmacologia , Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade
6.
Molecules ; 26(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34299393

RESUMO

The multi-target-directed ligands (MTDLs) strategy is encouraged for the development of novel modulators targeting multiple pathways in the neurodegenerative cascade typical for Alzheimer's disease (AD). Based on the structure of an in-house irreversible monoamine oxidase B (MAO-B) inhibitor, we aimed to introduce a carbamate moiety on the aromatic ring to impart cholinesterase (ChE) inhibition, and to furnish multifunctional ligands targeting two enzymes that are intricately involved in AD pathobiology. In this study, we synthesized three dual hMAO-B/hBChE inhibitors 13-15, with compound 15 exhibiting balanced, low micromolar inhibition of hMAO-B (IC50 of 4.3 µM) and hBChE (IC50 of 8.5 µM). The docking studies and time-dependent inhibition of hBChE confirmed the initial expectation that the introduced carbamate moiety is responsible for covalent inhibition. Therefore, dual-acting compound 15 represents an excellent starting point for further optimization of balanced MTDLs.


Assuntos
Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/química , Piperidinas/química , Inibidores da Colinesterase/química , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade
7.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207264

RESUMO

Despite not being utilized as considerably as other antidepressants in the therapy of depression, the monoamine oxidase inhibitors (MAOIs) proceed to hold a place in neurodegeneration and to have a somewhat broad spectrum in respect of the treatment of neurological and psychiatric conditions. Preclinical and clinical studies on MAOIs have been developing in recent times, especially on account of rousing discoveries manifesting that these drugs possess neuroprotective activities. The altered brain levels of monoamine neurotransmitters due to monoamine oxidase (MAO) are directly associated with various neuropsychiatric conditions like Alzheimer's disease (AD). Activated MAO induces the amyloid-beta (Aß) deposition via abnormal cleavage of the amyloid precursor protein (APP). Additionally, activated MAO contributes to the generation of neurofibrillary tangles and cognitive impairment due to neuronal loss. No matter the attention of researchers on the participation of MAOIs in neuroprotection has been on monoamine oxidase-B (MAO-B) inhibitors, there is a developing frame of proof indicating that monoamine oxidase-A (MAO-A) inhibitors may also play a role in neuroprotection. The therapeutic potential of MAOIs alongside the complete understanding of the enzyme's physiology may lead to the future advancement of these drugs.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/metabolismo , Animais , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Neurotransmissores/metabolismo
8.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281267

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson's disease. METHODS: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson's disease treatment, along with a manual search, and finally included a total of 116 publications in the review. RESULTS: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings. CONCLUSIONS: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.


Assuntos
Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/metabolismo , Antiparkinsonianos/farmacologia , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/farmacologia , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Genótipo , Humanos , Levodopa/efeitos adversos , Levodopa/metabolismo , Levodopa/farmacologia , Inibidores da Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Doença de Parkinson/metabolismo , Farmacogenética/métodos , Farmacogenética/tendências , Variantes Farmacogenômicos , Pesquisa Médica Translacional
9.
Exp Parasitol ; 226-227: 108121, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34097889

RESUMO

Cystic echinococcosis (CE), a parasitic larval cystic stage of a small taeniid-type tapeworm (Echinococcus granulosus), causes illness in intermediate hosts and has become a threat to global public health. Currently, chemical compounds recommended by the WHO targeting CE are albendazole and mebendazole, however, none of them shows enhanced efficacy. Novel molecular compounds are urgently required to treat this disease. Our group uncover a drug, termed harmine (HM), that may be capable of treating CE. In this study, we aim to evaluate the anti-parasitic efficacy and the mechanism of DNA damage of HM against E. granulosus. In vitro, the results indicated that, within two and three days of treatment, ABZ killed 30.4% and 35.3% of protoscoleces, whereas HM killed 52.7% and 100% of protoscoleces, respectively. Furthermore, the presence of abnormalities in the internal structure of protoscoleces was examined by ultrastructural images of TEM, and the result showed that there were scattered nucleoli and heterochromatin margination phenomenon by HM treatment. DNA damage of protoscoleces was examined by using the comet assay, and results showed the DNA of protoscoleces was damaged. Moreover, EgATM, EgP53, EgTopo2a and EgRad54 genes were used to support the DNA damage by HM treatment, and results showed that all four genes were upregulated expression. In further, the result of HM treatment was tested by using designed siRNA to inhibit the expression of EgTopo2a and EgRad54. The results demonstrated that the viability was 88.75 ± 2.11% after suppressing the expression of EgTopo2a, which was significantly higher than that for HM alone group (P < 0.01). The viability was 10.11 ± 2.60% after transfected with EgRad54 siRNA, which was significantly lower compared with the HM alone group (P < 0.01). Based on our preliminary data, HM demonstrated significant parasiticidal activity against E. granulosus in vitro without obvious toxicity towards its host cells, suggesting that HM can be a potential anti-echinococcosis drug. HM was found to induce DNA damages of CE by activating the EgATM-EgP53-EgTopo2a signaling pathway. We therefore surmise that DNA damage response may be one of the mechanisms of HM against the parasite.


Assuntos
Antiparasitários/farmacologia , Dano ao DNA/efeitos dos fármacos , Equinococose/tratamento farmacológico , Echinococcus granulosus/efeitos dos fármacos , Harmina/farmacologia , Animais , Antiparasitários/uso terapêutico , Ensaio Cometa , Echinococcus granulosus/genética , Echinococcus granulosus/ultraestrutura , Harmina/uso terapêutico , Microscopia Eletrônica de Transmissão , Inibidores da Monoaminoxidase/farmacologia , RNA Interferente Pequeno/química , RNA Interferente Pequeno/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Ovinos
10.
Eur J Med Chem ; 222: 113558, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34116327

RESUMO

Matrix metalloproteinase-9 (MMP-9) and monoamine oxidase-A (MAO-A) are central signaling nodes in CRC and promotors of distant metastasis associated with high mortality rates. Novel series of quinoxaline-based dual MMP-9/MAO-A inhibitors were synthesized to suppress CRC progression. The design rationale combines the thematic pharmacophoric features of MMP-9 and MAO-A inhibitors in hybrid scaffolds. All derivatives were initially screened via MTT assay for cytotoxic effects on normal colonocytes to assess their safety profiles, then evaluated for their anticancer potential on HCT116 cells overexpressing MMP-9 and MAO-A. The most promising derivatives 8, 16, 17, 19, and 28 exhibited single digit nanomolar IC50 against HCT116 cells within their safe doses (EC100) on normal colonocytes. They suppressed HCT116 cell migration by 73.32, 61.29, 21.27, 28.82, and 27.48%, respectively as detected by wound healing assay. Enzymatic assays revealed that the selected derivatives were superior to the reference MMP-9 and MAO-A inhibitors (quercetin and clorgyline, respectively). The nanomolar dual MMP-9/MAO-A inhibitor 19 was identified as the most potent and balanced dual inhibitor among the evaluated series with considerable selectivity against MAO-A over MAO-B. Besides, qRT-PCR analysis was conducted to explore the hit compounds' potential to downregulate hypoxia-inducing factor (HIF-1α) in HCT116 cells being correlated with MAO-A mediated CRC migration and invasion. The five above-mentioned compounds significantly downregulated HIF-1α by more than 5 folds. Docking simulations predicted their possible binding modes with MMP-9 and MAO-A and highlighted their essential structural features. Finally, they recorded drug-like in silico physicochemical parameters and ADMET profiles.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Desenho de Fármacos , Inibidores de Metaloproteinases de Matriz/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Quinoxalinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/química , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Quinoxalinas/síntese química , Quinoxalinas/química , Relação Estrutura-Atividade
12.
Nat Commun ; 12(1): 3530, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112755

RESUMO

Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.


Assuntos
Imunoterapia/métodos , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Neoplasias/tratamento farmacológico , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Linfoma/genética , Linfoma/metabolismo , Linfoma/mortalidade , Melanoma/genética , Melanoma/metabolismo , Melanoma/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Monoaminoxidase/deficiência , Monoaminoxidase/genética , Inibidores da Monoaminoxidase/uso terapêutico , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , RNA-Seq , Espécies Reativas de Oxigênio/metabolismo , Análise de Célula Única , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Biochem Mol Toxicol ; 35(8): e22833, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34047428

RESUMO

Some brain diseases are associated with oxidative stress and altered monoamine oxidase (MAO) activity. The objective of this study was to evaluate the antioxidant and neuroprotective actions through MAO inhibition of 3-(pyridin-2-yl)-2-(pyridine-2-ylimino) thiazolidin-4-one (PPIT, a synthetic molecule containing a thiazolidinone nucleus), as well as its effects on toxicity parameters in Swiss female mice. Five in vitro assays were carried out to verify the PPIT antioxidant capacity: protein carbonylation (PC), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 1,1-diphenyl-2-picryl-hydrazil (DPPH), ferric ion (Fe3+ ) reducing antioxidant power (FRAP), and superoxide dismutase (SOD)-like activity. The results showed that PPIT reduced the level of PC in the homogenate of the brain. This compound did not demonstrate SOD mimetic activity, but it acted as a free radical scavenger (ABTS and DPPH) and exhibited reducing activity in the FRAP assay. In addition, the effects of PPIT on cerebral MAO activity (MAO-A and B isoforms) were investigated in vitro. Our data revealed inhibition of the MAO-B activity by PPIT with no effects on MAO-A. Lastly, an acute oral toxicity test was conducted in mice. No changes in food intake, body weight, and biochemical markers of kidney and liver damage were detected in mice treated with a high dose of PPIT (300 mg/kg). In conclusion, the present study demonstrated that PPIT exhibits antioxidant activity and selectively inhibits the MAO-B isoform without causing apparent toxicity. These findings suggest PPIT as a potential therapeutic candidate to be tested in preclinical models of brain diseases involving perturbations of MAO-B activity and redox status.


Assuntos
Encéfalo/enzimologia , Sequestradores de Radicais Livres/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Animais , Encefalopatias/tratamento farmacológico , Encefalopatias/enzimologia , Feminino , Sequestradores de Radicais Livres/efeitos adversos , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Masculino , Camundongos , Inibidores da Monoaminoxidase/efeitos adversos , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química
14.
Eur J Neurosci ; 54(3): 4729-4739, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34022091

RESUMO

Isatin is a biofactor with different biochemical and pharmacological properties whose effects attract much attention because it is an endogenous inhibitor of the monoamine oxidase in the brain. When exogenously administrated, isatin increases dopamine levels in intact and denervated striatum of rats, an effect that could indicate its potential as a therapeutic agent in Parkinson disease. However, the neurochemical mechanisms by which isatin increases dopamine in the striatum are poorly understood. In the present study, we evaluate the role of the glutamatergic and nitrergic systems in the isatin-induced dopamine release from rat striatum. Our findings show that the intrastriatal administration of 10 mM isatin significantly increases the in vivo release of dopamine (1,104.7% ± 97.1%), and the amino acids glutamate (428.7% ± 127%) and taurine (221% ± 22%) from rat striatum measured by brain microdialysis. The pretreatment with MK-801 (500 µM) or AP5 (650 µM) (glutamatergic NMDA receptors antagonists) significantly reduces the effect of isatin on dopamine release by 52% and 70.5%, respectively. The administration of the nitric oxide synthase inhibitors, L-NAME (100 µM) or 7-NI (100 µM) also decreases the isatin-induced dopamine release by 77% and 42%, respectively. These results show that isatin, in addition to increasing dopamine release, also increases glutamate levels, and possibly activates NMDA receptors and nitric oxide production, which can promote a further increase in the dopamine release.


Assuntos
Dopamina , Isatina , Animais , Corpo Estriado , Isatina/farmacologia , Microdiálise , Inibidores da Monoaminoxidase/farmacologia , Óxido Nítrico Sintase , Ratos , Ratos Sprague-Dawley
15.
Bioorg Chem ; 111: 104895, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33887586

RESUMO

A series of 4-aminoalkyl-1(2H)-phthalazinone derivatives was designed and synthesized as potential multifunctional agents for Alzheimer's disease (AD) treatment. In vitro biological assay results demonstrated that most synthesized compounds exhibited significant AChE inhibition, moderate to high MAOs inhibitory potencies and good anti-platelet aggregation abilities. Among them, compound 15b exhibited the highest inhibitory potencies towards MAO-B and MAO-A (IC50 = 0.7 µM and 6.4 µM respectively), moderate inhibition towards AChE (IC50 = 8.2 µM), and good activities against self- and Cu2+-induced Aß1-42 aggregation and platelet aggregation. Moreover, 15b also displayed antioxidant capacity, neuroprotective potency, anti-neuroinflammation and BBB permeability. These excellent results indicated that compound 15b could be worthy of further studies to be considered as a promising multifunctional candidate for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Ftalazinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Humanos , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Ftalazinas/síntese química , Ftalazinas/química , Agregação Plaquetária/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
16.
Psychopharmacology (Berl) ; 238(8): 2105-2120, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33837810

RESUMO

BACKGROUND: Depression causes significant debilitating symptoms and economic burden. Current management is challenged by slow onset of action and modest efficacies of antidepressants; thus, the search for newer antidepressants remains relevant. We evaluated the antidepressant effects of a kaurene diterpene, xylopic acid (XA), in zebrafish and mouse models. METHODS: The chronic unpredictable stress (CUS) protocol in zebrafish and the tail suspension test (TST), forced swim test (FST), lipopolysaccharide-induced depression-like behaviour test (LID) and repeated open space swimming test (OSST) in mice were used. We further examined the impact of depleting monoamines on XA's antidepressant effects. The contribution of glutamatergic and nitrergic pathways on the antidepressant effect of XA in mice and XA's effects on 5-HT receptors and monoamine oxidase (MAO) enzymes were also evaluated. Finally, XA's influence on neuroprotection was evaluated by measuring BDNF and oxidative stress enzymes in whole brain. XA doses (1-10 µM) in zebrafish and (10, 30, 100 mg kg-1) in mice exerted potent antidepressant-like potential in FST, TST, LID and showed fast-onset antidepressant-like property in the OSST. RESULTS: The antidepressant-like properties in mice were reversed by blocking synthesis/release of serotonin but not noradrenaline using p-chlorophenylalanine and α-methyl-p-tyrosine, respectively. This antidepressant-like effect was potentiated by D-cycloserine and Nω-Nitro-L-arginine methyl ester (L-NAME) but not by D-serine and L-arginine. XA also evoked partial agonist-like effects on 5-hydroxytrptamine receptors on the rat fundus but it did not have MAO inhibition effect. It also increased BDNF, glutathione and antioxidant enzymes. CONCLUSION: Therefore, xylopic acid possesses antidepressant-like effects largely mediated by serotonergic and neuroprotective mechanisms.


Assuntos
Antidepressivos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/tratamento farmacológico , Diterpenos do Tipo Caurano/uso terapêutico , Serotonina/metabolismo , Animais , Antidepressivos/farmacologia , Depressão/metabolismo , Depressão/psicologia , Diterpenos do Tipo Caurano/farmacologia , Relação Dose-Resposta a Droga , Elevação dos Membros Posteriores/efeitos adversos , Elevação dos Membros Posteriores/psicologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Natação/psicologia , Peixe-Zebra
17.
Molecules ; 26(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33921982

RESUMO

Fourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an α,ß-unsaturated ketone were synthesized. These compounds may be designated as chalcocoumarins (3-cinnamoyl-2H-chromen-2-ones). Both chalcones and coumarins are recognized scaffolds in medicinal chemistry, showing diverse biological and pharmacological properties among which neuroprotective activities and multiple enzyme inhibition, including mitochondrial enzyme systems, stand out. The evaluation of monoamine oxidase B (MAO-B) inhibitors has aroused considerable interest as therapeutic agents for neurodegenerative diseases such as Parkinson's. Of the fourteen chalcocumarins evaluated here against MAO-B, ChC4 showed the strongest activity in vitro, with IC50 = 0.76 ± 0.08 µM. Computational docking, molecular dynamics and MM/GBSA studies, confirm that ChC4 binds very stably to the active rMAO-B site, explaining the experimental inhibition data.


Assuntos
Chalconas/química , Cumarínicos/química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/química , Animais , Sítios de Ligação , Relação Dose-Resposta a Droga , Humanos , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Ratos , Relação Estrutura-Atividade
18.
Eur J Pharm Sci ; 162: 105821, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33781856

RESUMO

DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1a) is highly expressed in glioma, an aggressive brain tumor, and has been proposed as a therapeutic target for cancer. In the current study, we have used an optimized and validated time-resolved fluorescence energy transfer (TR-FRET)-based DYRK1A assay for high-throughput screening (HTS) in 384-well format. A small-scale screen of the FDA-approved Prestwick drug collection identified the ß-carboline, harmine, and four related analogs as DYRK1A inhibitors. Hits were confirmed by dose response and in an orthogonal DYRK1A assay. Harmine's potential therapeutic use has been hampered by its off-target activity for monoamine oxidase A (MAO-A) which impacts multiple nervous system targets. Selectivity profiling of harmine and a broader collection of analogs allowed us to map some divergent SAR (structure-activity relationships) for the DYRK1A and MAO-A activities. The panel of harmine analogs had varying activities in vitro in glioblastoma (GBM) cell lines when tested for anti-proliferative effects using a high content imaging assay. In particular, of the identified analogs, harmol was found to have the best selectivity for DYRK1A over MAO-A and, when tested in a glioma tumor xenograft model, harmol demonstrated a better therapeutic window compared to harmine.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Monoaminoxidase , Neoplasias , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Carbolinas , Harmina/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Monoaminoxidase , Inibidores da Monoaminoxidase/farmacologia
19.
Environ Sci Pollut Res Int ; 28(29): 38855-38866, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33743158

RESUMO

Eleven piperazine-containing 1,3-diphenylprop-2-en-1-one derivatives (PC1-PC11) were evaluated for their inhibitory activities against monoamine oxidases (MAOs), cholinesterases (ChEs), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with a view toward developing new treatments for neurological disorders. Compounds PC10 and PC11 remarkably inhibited MAO-B with IC50 values of 0.65 and 0.71 µM, respectively. Ten of the eleven compounds weakly inhibited AChE and BChE with > 50% of residual activities at 10 µM, although PC4 inhibited AChE by 56.6% (IC50 = 8.77 µM). Compound PC3 effectively inhibited BACE-1 (IC50 = 6.72 µM), and PC10 and PC11 moderately inhibited BACE-1 (IC50 =14.9 and 15.3 µM, respectively). Reversibility and kinetic studies showed that PC10 and PC11 were reversible and competitive inhibitors of MAO-B with Ki values of 0.63 ± 0.13 and 0.53 ± 0.068 µM, respectively. ADME predictions for lead compounds revealed that PC10 and PC11 have central nervous system (CNS) drug-likeness. Molecular docking simulations showed that fluorine atom and trifluoromethyl group on PC10 and PC11, respectively, interacted with the substrate cavity of the MAO-B active site. Our results suggested that PC10 and PC11 can be considered potential candidates for the treatment of neurological disorders such as Alzheimer's disease and Parkinson's disease.


Assuntos
Doença de Alzheimer , Chalconas , Doença de Alzheimer/tratamento farmacológico , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Humanos , Cinética , Simulação de Acoplamento Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Piperazina , Relação Estrutura-Atividade
20.
Bioorg Chem ; 109: 104685, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33640631

RESUMO

The monoamine oxidase-B (MAO-B) inhibitors with neuroprotective effects are better for Parkinson's disease (PD) treatment, due to the complicated pathogenesis of PD. To develop new hMAO-B inhibitors with neuroprotection, a novel series of 3,4-dihydrocoumarins was designed as selective and reversible hMAO-B inhibitors to treat PD. Most compounds showed potent and selective inhibition for hMAO-B over hMAO-A with IC50 values ranging from nanomolar to sub-nanomolar. Among them, compound 4d was the most potent hMAO-B inhibitor (IC50 = 0.37 nM) being about 20783-fold more active than iproniazid, and exhibited the highest selectivity for hMAO-B (SI > 270,270). Kinetic studies revealed that compound 4d was a reversible and competitive inhibitor of hMAO-B. Neuroprotective studies indicated that compound 4d could protect PC12 cells from the damage induced by 6-OHDA and rotenone. Besides, compound 4d did not exhibit acute toxicity at a dose up to 2500 mg/kg (po), and could cross the BBB in parallel artificial membrane permeability assay. More importantly, compound 4d was able to significantly prevent the motor deficits in the MPTP-induced PD model. These results indicate that compound 4d is an effective and promising candidate against PD.


Assuntos
Cumarínicos/química , Desenho de Fármacos , Intoxicação por MPTP/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Animais , Indanos/farmacologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/química , Oxidopamina/toxicidade , Células PC12 , Conformação Proteica , Ratos , Rotenona/toxicidade , Relação Estrutura-Atividade
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