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1.
Molecules ; 28(19)2023 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-37836759

RESUMO

Fourteen quinolizidine derivatives, structurally related to the alkaloids lupinine and cytisine and previously studied for other pharmacological purposes, were presently tested for antiarrhythmic, and other cardiovascular effects on isolated guinea pig heart tissues in comparison to well-established reference drugs. According to their structures, the tested compounds are assembled into three subsets: (a) N-(quinolizidinyl-alkyl)-benzamides; (b) 2-(benzotriazol-2-yl)methyl-1-(quinolizidinyl)alkyl-benzimidazoles; (c) N-substituted cytisines. All compounds but two displayed antiarrhythmic activity that was potent for compounds 4, 1, 6, and 5 (in ascending order). The last compound (N-(3,4,5-trimethoxybenzoyl)aminohomolupinane) was outstanding, exhibiting a nanomolar potency (EC50 = 0.017 µM) for the increase in the threshold of ac-arrhythmia. The tested compounds shared strong negative inotropic activity; however, this does not compromise the value of their antiarrhythmic action. On the other hand, only moderate or modest negative chronotropic and vasorelaxant activities were commonly observed. Compound 5, which has high antiarrhythmic potency, a favorable cardiovascular profile, and is devoid of antihypertensive activity in spontaneously hypertensive rats, represents a lead worthy of further investigation.


Assuntos
Alcaloides , Quinolizidinas , Esparteína , Ratos , Animais , Cobaias , Quinolizidinas/farmacologia , Antiarrítmicos/farmacologia , Antiarrítmicos/química , Coração , Esparteína/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Alcaloides/farmacologia
2.
Phytother Res ; 35(4): 2145-2156, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33295076

RESUMO

Ellagitannins may have a beneficial impact in cardiovascular diseases. The aim of the study was to evaluate the effect of high-fat diet (HFD) and the efficacy of Castanea sativa Mill. bark extract (ENC) on cardiac and vascular parameters. Rats were fed with regular diet, (RD, n = 15), HFD (n = 15), RD + ENC (20 mg/kg/day by gavage, n = 15), and HFD + ENC (same dose, n = 15) and the effects on body weight, biochemical serum parameters, and inflammatory cytokines determined. Cardiac functional parameters and aorta contractility were also assessed on isolated atria and aorta. Results showed that ENC reduced weight gain and serum lipids induced by HFD. In in vitro assays, HFD decreased the contraction force of left atrium, increased right atrium chronotropy, and decreased aorta K+ -induced contraction; ENC induced transient positive inotropic and negative chronotropic effects on isolated atria from RD and HFD rats and a spasmolytic effect on aorta. In ex vivo experiments, ENC reverted inotropic and chronotropic changes induced by HFD and enhanced Nifedipine effect more on aorta than on heart. In conclusion, ENC restores metabolic dysfunction and cardiac cholinergic muscarinic receptor function, and exerts spasmolytic effect on aorta in HFD rats, highlighting its potential as nutraceutical tool in obesity.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Casca de Planta/química , Extratos Vegetais/química , Taninos/química , Animais , Modelos Animais de Doenças , Masculino , Ratos
3.
Int J Mol Sci ; 21(6)2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32204339

RESUMO

The research for innovative treatments against colon adenocarcinomas is still a great challenge. Acacia catechu Willd. heartwood extract (AC) has health-promoting qualities, especially at the gastrointestinal level. This study characterized AC for its catechins content and investigated the apoptosis-enhancing effect in human colorectal adenocarcinoma HT-29 cells, along with its ability to spare healthy tissue. MTT assay was used to describe the time course, concentration dependence and reversibility of AC-mediated cytotoxicity. Cell cycle analysis and AV-PI and DAPI-staining were performed to evaluate apoptosis, together with ROS formation, mitochondrial membrane potential (MMP) changes and caspase activities. Rat ileum and colon rings were tested for their viability and functionality to explore AC effects on healthy tissue. Quantitative analysis highlighted that AC was rich in (±)-catechin (31.5 ± 0.82 mg/g) and (-)-epicatechin (12.5 ± 0.42 mg/g). AC irreversibly decreased cell viability in a concentration-dependent, but not time-dependent fashion. Cytotoxicity was accompanied by increases in apoptotic cells and ROS, a reduction in MMP and increases in caspase-9 and 3 activities. AC did not affect rat ileum and colon rings' viability and functionality, suggesting a safe profile toward healthy tissue. The present findings outline the potential of AC for colon cancer treatment.


Assuntos
Acacia/química , Apoptose/efeitos dos fármacos , Catequina/farmacologia , Extratos Vegetais/farmacologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Caspase 3/metabolismo , Caspase 9/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Células HT29 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo
4.
Molecules ; 25(5)2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32120861

RESUMO

Our research groups have been involved for many years in studies aimed at identifying new active organic compounds endowed with pharmacological properties. In this work, we focused our attention on the evaluation of cardiovascular and molecular drug resistance (MDR) reverting activities of some nitrosubstituted sulphur-containing heterocycles. Firstly, we have examined the effects of 4-nitro-3-(4-methylphenyl)-3,6-dihydro-2H-thiopyran S,S-dioxide 5, and have observed no activity. Then we have extended our investigation to the 3-aryl-4-nitrobenzothiochromans S,S-dioxide 6 and 7, and have observed an interesting biological profile. Cardiovascular activities were assessed for all compounds using ex vivo studies, while the MDR reverting effect was evaluated only for selected compounds using tumor cell lines. All compounds were shown to affect cardiovascular parameters. Compound 7i exerted the most effect on negative inotropic activity, while 6d and 6f could be interesting molecules for the development of more active ABCB1 inhibitors. Both 6 and 7 represent structures of large possible biological interest, providing a scaffold for the identification of new ABCB1 inhibitors.


Assuntos
Antineoplásicos/farmacologia , Canais de Cálcio/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromanos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Canais de Cálcio/metabolismo , Linhagem Celular Tumoral , Cromanos/síntese química , Cromanos/química , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Cobaias , Átrios do Coração/metabolismo , Humanos , Concentração Inibidora 50 , Músculo Liso/fisiologia , Piranos/síntese química , Piranos/química , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Tiamina/análogos & derivados , Tiamina/síntese química , Tiamina/química , Tiamina/farmacologia
5.
J Cell Biochem ; 118(4): 839-850, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27739104

RESUMO

Ischemic brain injury is one of the most important causes of death worldwide. The use of one-drug-multi-target agents based on natural compounds is a promising therapeutic option for cerebral ischemia due to their pleiotropic properties. This study assessed the neuroprotective properties of Castanea sativa Mill. bark extract (ENC) in human astrocytoma U-373 MG cells subjected to oxygen-glucose deprivation and reperfusion and rat cortical slices subjected to ischemia-like conditions or treated with glutamate or hydrogen peroxide. Neuroprotective effects were determined by assessing cells or slices viability (MTT assay), ROS formation (DCFH-DA assay), apoptosis (sub G0/G1 peak), nuclear fragmentation and chromatin condensation (DAPI staining) as well as changes in lysosomes and mitochondria morphology (Acridine Orange and Rhodamine123 staining, respectively). ENC treatment before injury on U-373 MG cells (5-50 µg/ml) and cortical slices (50-100 µg/ml) provided neuroprotection, while lower or higher concentrations (100 µg/ml U-373 MG cells, 200 µg/ml brain slices) were ineffective. ENC addition during reperfusion or after the injury was not found to be effective. The results suggest that ENC might hold potential as preventive neuroprotective agent, and indicate the importance of further studies exploring its mechanism of action. J. Cell. Biochem. 118: 839-850, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Isquemia Encefálica/prevenção & controle , Fagaceae , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Fagaceae/química , Ácido Glutâmico/toxicidade , Humanos , Peróxido de Hidrogênio/toxicidade , Técnicas In Vitro , Masculino , Fármacos Neuroprotetores/química , Fitoterapia , Casca de Planta/classificação , Extratos Vegetais/química , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
6.
Ultrastruct Pathol ; 41(2): 147-153, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28277149

RESUMO

Castanea sativa Mill (ENC®), containing tannins against 33 Chlamydia strains, was compared to SMAP-29 with inhibitory effect against C. trachomatis and C. pneumoniae. The ENC® activity against Chlamydia spp. was evaluated determining the lowest concentration to achieve more than half reduction of intact chlamydial inclusions versus controls. ENC® reduced all Chlamydia strains tested at 1 µg/mL, while SMAP-29 induced reductions of C. trachomatis and C. pneumoniae infectivity at 10 µg/mL. A great reduction of C. trachomatis, C. pneumoniae, and C. abortus infectivity was achieved with a 10 µg/mL ENC® concentration, whereas their infectivity was almost inhibited at 100 µg/mL ENC® concentration.


Assuntos
Anti-Infecciosos/farmacologia , Chlamydia/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Linhagem Celular , Chlamydia/ultraestrutura , Técnicas In Vitro , Macaca mulatta , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Transmissão , Casca de Planta
7.
J Cell Biochem ; 117(2): 510-20, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26240013

RESUMO

One of the major features of neurodegenerative disease is the selective vulnerability of different neuronal populations that are affected in a progressive and often stereotyped manner. Despite the susceptible neuronal population varies between diseases, oxidative stress is implicated as the major pathogenic process in all of them. Natural Extract of Castanea sativa Mill. bark (ENC), recently characterized in its phenolic composition, acts as antioxidant and cardioprotective agent. Its neuroprotettive properties, however, have never been investigated. The aim of this study was to assess neuroprotection of ENC in in vitro models of oxidative-stress-mediate injury. Human neuroblastoma SH-SY5Y cells treated with glutamate (50 mM for 24 h) or hydrogen peroxide (25 µM for 1 h followed by 24 with medium) were used. The results showed that the addition of ENC (1-50 µg/ml) to cell medium before the neuronal damage provided neuroprotection in both experimental models used, while its addition after the injury was ineffective. In conclusion, the present results suggest that ENC could be a valuable support as dietary supplement, combining beneficial preventive neuroprotettive effects with a high antioxidant activity.


Assuntos
Fagaceae/química , Estresse Oxidativo , Casca de Planta/química , Extratos Vegetais/farmacologia , Linhagem Celular Tumoral , Forma Celular , Sobrevivência Celular , Avaliação Pré-Clínica de Medicamentos , Ácido Glutâmico/toxicidade , Humanos , Peróxido de Hidrogênio/farmacologia , Concentração Inibidora 50 , Neuroblastoma , Fármacos Neuroprotetores/farmacologia
8.
Molecules ; 19(10): 16543-72, 2014 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-25317581

RESUMO

As a result of the ring-into-ring conversion of nitrosoimidazole derivatives, we obtained a molecular scaffold that, when properly decorated, is able to decrease inotropy by blocking L-type calcium channels. Previously, we used this scaffold to develop a quantitative structure-activity relationship (QSAR) model, and we used the most potent oxadiazolothiazinone as a template for ligand-based virtual screening. Here, we enlarge the diversity of chemical decorations, present the synthesis and in vitro data for 11 new derivatives, and develop a new 3D-QSAR model with recent in silico techniques. We observed a key role played by the oxadiazolone moiety: given the presence of positively charged calcium ions in the transmembrane channel protein, we hypothesize the formation of a ternary complex between the oxadiazolothiazinone, the Ca2+ ion and the protein. We have supported this hypothesis by means of pharmacophore generation and through the docking of the pharmacophore into a homology model of the protein. We also studied with docking experiments the interaction with a homology model of P-glycoprotein, which is inhibited by this series of molecules, and provided further evidence toward the relevance of this scaffold in biological interactions.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Compostos Heterocíclicos/química , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Cobaias , Átrios do Coração/efeitos dos fármacos , Simulação de Acoplamento Molecular , Músculo Liso/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Homologia Estrutural de Proteína
9.
Org Biomol Chem ; 10(45): 8994-9003, 2012 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-23073236

RESUMO

In the framework of our interest in racemic thiazinooxadiazol-3-ones we determined the absolute configuration and the biological activity as L-type calcium channel blockers of two compounds that differ in the length of the acetal chain, which could affect the pharmacological profile. We observed an interesting inversion of the stereoselectivity, with the activity residing on the R-form for a short chain compound (n = 1) and on the S-form for a long chain one (n = 12). The length of the linear acetal chain appears to be able to invert the stereoselectivity of such a class of compounds, and in silico simulations suggested that this different behaviour might be explained by different hydrophilic and hydrophobic interactions with the binding site.


Assuntos
Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/metabolismo , Oxidiazóis/química , Oxidiazóis/farmacologia , Elétrons , Modelos Moleculares , Conformação Molecular , Estereoisomerismo
10.
Invest New Drugs ; 29(1): 98-109, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19876599

RESUMO

We report herein the reversal of multidrug resistance-1 (MDR1) in A2780/DX3 cells by the two nifedipine-like compounds 1 and 2 that are part of a library of 1,4-dihydropyridines (1,4-DHPs) calcium-channel modulators bearing in C-4 a different substituted imidazo[2,1-b]thiazole system. By methylthiazol tetrazolium (MTT) assay, cytofluorimetry, and fluorescence microscopy we evaluated their ability to reverse MDR in our cell system. Moreover, together with compound 3 (the diltiazem-like 8-(4-chlorophenyl)-5-methyl-8-[(2Z)-pent-2-en-1-yloxy]-8H-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one) we analyzed their ability to potentiate the triggering of apoptosis after exposure to doxorubicin, through the nuclear morphological analysis after 4',6-diamidino-2-phenylindole (DAPI), the fluorescein isothiocyanate (FITC)-Annexin-V/propidium iodide (PI) staining and the caspase activity determination. Our results demonstrate that compounds 1 and 2, at concentrations showing a very low (5%) or absent inhibition of cell proliferation, in combination with doxorubicin enhance its antiproliferative activity (from 30% to 54% IC(50) reduction) in A2780/DX3 cells through an increase of doxorubicin intracellular accumulation. These compounds together with compound 3, which has already been demonstrated to act as a potent inhibitor of MDR1 function, were also able to significantly potentiate the activation of the apoptosis machinery triggered by the exposure to doxorubicin. In conclusion, our results identify two new molecules structurally related to the calcium-channel blocker nifedipine, but characterized by a very low LTCC blockers activity, able to potentiate the antiproliferative and apoptotic activities of doxorubicin through an increase of its intracellular concentration likely caused by the inhibition of MDR1 function.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Diltiazem/análogos & derivados , Diltiazem/farmacologia , Nifedipino/análogos & derivados , Nifedipino/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Anexina A5/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Diltiazem/química , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Citometria de Fluxo , Humanos , Indóis/metabolismo , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Nifedipino/química , Propídio/metabolismo , Coloração e Rotulagem
11.
Antioxidants (Basel) ; 9(9)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882797

RESUMO

Oxidative stress (OS) arising from tissue redox imbalance, critically contributes to the development of neurodegenerative disorders. Thus, natural compounds, owing to their antioxidant properties, have promising therapeutic potential. Pres phytum (PRES) is a nutraceutical product composed of leaves- and flowers-extracts of Olea europaea L. and Hibiscus sabdariffa L., respectively, the composition of which has been characterized by HPLC coupled to a UV-Vis and QqQ-Ms detector. As PRES possess antioxidant, antiapoptotic and anti-inflammatory properties, the aim of this study was to assess its neuroprotective effects in human neuroblastoma SH-SY5Y cells and in rat brain slices subjected to OS. PRES (1-50 µg/mL) reverted the decrease in viability as well as the increase in sub-diploid-, DAPI-and annexin V-positive-cells, reduced ROS formation, recovered the mitochondrial potential and caspase-3 and 9 activity changes caused by OS. PRES (50-100 µg/mL) neuroprotective effects occurred also in rat brain slices subjected to H2O2 challenge. Finally, as the neuroprotective potential of PRES is strictly related to its penetration into the brain and a relatively good pharmacokinetic profile, an in-silico prediction of its components drug-like properties was carried out. The present results suggest the possibility of PRES as a nutraceutical, which could help in preventing neurodegenerative diseases.

12.
Antioxidants (Basel) ; 9(11)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33182461

RESUMO

The petals of the saffron crocus (Crocus sativus L.) are considered a waste material in saffron production, but may be a sustainable source of natural biologically active substances of nutraceutical interest. The aim of this work was to study the cardiovascular effects of kaempferol and crocin extracted from saffron petals. The antiarrhythmic, inotropic, and chronotropic effects of saffron petal extract (SPE), kaempferol, and crocin were evaluated through in vitro biological assays. The antioxidant activity of kaempferol and crocin was investigated through the 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay using rat cardiomyoblast cell line H9c2. The MTT assay was applied to assess the effects of kaempferol and crocin on cell viability. SPE showed weak negative inotropic and chronotropic intrinsic activities but a significant intrinsic activity on smooth muscle with a potency on the ileum greater than on the aorta: EC50 = 0.66 mg/mL versus EC50 = 1.45 mg/mL. Kaempferol and crocin showed a selective negative inotropic activity. In addition, kaempferol decreased the contraction induced by KCl (80 mM) in guinea pig aortic and ileal strips, while crocin had no effect. Furthermore, following oxidative stress, both crocin and kaempferol decreased intracellular ROS formation and increased cell viability in a concentration-dependent manner. The results indicate that SPE, a by-product of saffron cultivation, may represent a good source of phytochemicals with a potential application in the prevention of cardiovascular diseases.

13.
Biomolecules ; 10(6)2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32512899

RESUMO

A new Thymus vulgaris L. solid essential oil (SEO) formulation composed of liquid EO linked to solid excipients has been chemically analysed and evaluated for its intestinal spasmolytic and antispastic effects in ex vivo ileum and colon of guinea pig and compared with liquid EO and excipients. Liquid EO and solid linked EO were analysed by original capillary electrochromatography coupled to diode array detection (CEC-DAD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodologies. The main bioactive constituents are thymol and carvacrol, with minor constituents for a total of 12 selected analysed compounds. Liquid EO was the most effective in decreasing basal contractility in ileum and colon; excipients addiction permitted normal contractility pattern in solid linked EO SEO. In ileum and colon, the Thymus vulgaris L. solid formulation exerted the relaxant activity on K+-depolarized intestinal smooth muscle as well as liquid EO. The solid essential oil exhibits antimicrobial activity against different strains (Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa, Escherichia coli, Salmonella Thyphimurium, Candida albicans) similarly to liquid oil, with activity against pathogen, but not commensal strains (Bifidobacterium Breve, Lactobacillus Fermentum) in intestinal homeostasis. Therefore, Thymus vulgaris L. solid essential oil formulation can be proposed as a possible spasmolytic and antispastic tool in medicine.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Contração Muscular/efeitos dos fármacos , Óleos Voláteis/farmacologia , Parassimpatolíticos/farmacologia , Thymus (Planta)/química , Animais , Antibacterianos/análise , Antifúngicos/análise , Bifidobacterium breve/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Composição de Medicamentos , Escherichia coli/efeitos dos fármacos , Cobaias , Limosilactobacillus fermentum/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Estrutura Molecular , Óleos Voláteis/análise , Parassimpatolíticos/análise , Pseudomonas aeruginosa/efeitos dos fármacos , Salmonella/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos
14.
Pharmacol Rep ; 71(1): 128-132, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30550993

RESUMO

BACKGROUND: Constitutive (agonist-independent) activity is a prerogative of many G protein-coupled receptors (GPCRs) including α1-adrenoceptors (α1-ARs). Inhibition of such an activity at α1-AR subtypes by antagonists with negative efficacy is difficult to be adequately tested. METHODS: In the present experimental approach, we compared the activity of three calcium channel blockers (nifedipine, diltiazem and verapamil) and of three potent benzodioxane-based α1-AR antagonists, differing for subtype selectivity and inverse agonist properties, in producing smooth muscle relaxation and negative inotropy under the same test conditions. We selected, as benzodioxane derivatives, (S)-WB4101, inverse agonist with slight α1A/α1B-α1D AR selectivity, and two previously developed analogues. Both of these are potent antagonists at α1D-AR, that is the α1- AR subtype suspected of the highest susceptibility to inverse agonists for its high degree of basal activity, but only one is inverse agonist. RESULTS: We found that all the three benzodioxane-related α1-AR antagonists have significant intrinsic relaxant activity on non-vascular smooth muscle and moderate negative inotropic effect, while they do not relax aorta. Their potency is always lower than that of three calcium channel blockers. CONCLUSIONS: Intrinsic myorelaxant and negative inotropic activity of the three benzodioxane-based α1-AR antagonist is related neither to a particular profile of α1-AR subtype selectivity nor to whether or not being an inverse agonist, but it parallels the calcium antagonists effects indicating a direct interaction of the three α1-AR antagonists with L-type Ca2+ channels.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Dioxanos/farmacologia , Músculo Liso/efeitos dos fármacos , Miocárdio , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 1/química , Animais , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Dioxanos/química , Agonismo Inverso de Drogas , Feminino , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Estrutura Molecular , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Relação Estrutura-Atividade
15.
J Med Chem ; 51(6): 1592-600, 2008 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-18303827

RESUMO

The synthesis, characterization, and functional in vitro assays in cardiac tissues and smooth muscle (vascular and nonvascular) of a number of 4-imidazo[2,1- b]thiazole-1,4-dihydropyridines are reported. The binding properties for the novel compounds have been investigated and the interaction with the binding site common to other aryl-dihydropyridines has been demonstrated. Interestingly, the novel 4-aryl-dihydropyridines are L-type calcium channel blockers with a peculiar pharmacological behavior. Indeed, the imidazo[2,1- b]thiazole system is found to confer to the dihydropyridine scaffold an inotropic and/or chronotropic cardiovascular activity with a high selectivity toward the nonvascular tissue. Finally, molecular modeling studies were undertaken for the most representative compounds with the aim of describing the binding properties of the new ligands at molecular level and to rationalize the found structure-activity relationship data. Due to the observed pharmacological behavior of our compounds, they might be promising agents for the treatment of specific cardiovascular pathologies such as cardiac hypertrophy and ischemia.


Assuntos
Di-Hidropiridinas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Coração/efeitos dos fármacos , Imidazóis/farmacologia , Contração Miocárdica/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Sítios de Ligação , Simulação por Computador , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Cobaias , Imidazóis/síntese química , Imidazóis/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Músculo Liso Vascular/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
16.
PLoS One ; 13(8): e0201540, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30080863

RESUMO

The effects of Castanea sativa Mill. have been studied in high fat diet (HFD) overweight rats. Natural Extract of Chestnut bark (Castanea sativa Mill.) (ENC®), rich in ellagitannins, has been studied in 120 male Sprague-Dawley rats, divided in four groups. Two groups were controls: regular (RD) and HDF diet. Two groups received ENC® (20 mg/kg/day): RD + ENC® and HFD + ENC®. At baseline and at 7, 14 and 21 days, weight gain, serum lipids, plasma cytokines, liver histology, microsomial enzymes and oxidation, intestinal oxidative stress and contractility were studied. HFD increased body weight, increased pro-inflammatory cytokines, induced hepatocytes microvescicular steatosis, altered microsomial, increased liver and intestinal oxidative stress, deranged intestinal contractility. In HFD-fed rats, ENC® exerted antiadipose and antioxidative activities and normalized intestinal contractility, suggesting a potential approach to overweight management associated diseases.


Assuntos
Fagaceae/química , Mucosa Intestinal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Obesidade/prevenção & controle , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Mucosa Intestinal/metabolismo , Fígado/patologia , Masculino , Obesidade/etiologia , Obesidade/patologia , Estresse Oxidativo/efeitos dos fármacos , Casca de Planta/química , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/uso terapêutico , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Aumento de Peso/efeitos dos fármacos
17.
J Med Chem ; 50(2): 334-43, 2007 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-17228875

RESUMO

Eighteen analogues of lidocaine, mexiletine, and procainamide were synthesized, replacing their aminoalkyl chains with the rigid and cumbersome quinolizidine nucleus. The target compounds were tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. Most compounds exhibited from moderate to high antiarrhythmic activity, and compounds 7, 9, and 19 were more active and potent than quinidine and lidocaine, while producing only modest inotropic, chronotropic, and vasorelaxant effects. These compounds were studied on spontaneously beating Langendorff-perfused gp heart. While quinidine and amiodarone produced a dose-dependent prolongation of all the ECG intervals, compounds 7, 9, and 19, even at concentrations 10-20 times higher than EC50 for the antiarrhythmic activity, only moderately prolonged the PR and QT intervals, leaving unchanged the QRS complex. Ether 7 deserves further investigations due to its interesting cardiovascular profile.


Assuntos
Antiarrítmicos/síntese química , Quinolizinas/síntese química , Amiodarona/farmacologia , Animais , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Eletrocardiografia , Feminino , Cobaias , Frequência Cardíaca , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Lidocaína/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Contração Miocárdica/efeitos dos fármacos , Procainamida/farmacologia , Quinidina/farmacologia , Quinolizinas/química , Quinolizinas/farmacologia , Estimulação Química , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacos
18.
J Med Food ; 20(6): 592-600, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28422543

RESUMO

Acacia catechu Willd. is a plant diffused in India and other Asian countries, where it is used as a traditional medicine for the treatment of several ailments including diarrhea, one of the most common pathologies worldwide. In this study, we determined the chemical composition of Acacia catechu Willd. extract (AC) and evaluated its effect on spontaneous and induced contractility in isolated guinea pig ileum and proximal colon. Preliminary data about its antimicrobial effect against some pathogen agents versus some microbiota intestinal strain have been also reported. Chemical analysis revealed the presence of catechins, such as (-)-Epicatechin and (+)-Catechin. AC extract reduced frequency and amplitude of colon smooth muscle spontaneous contractility, in a concentration-dependent manner. A weaker effect of the extract was exerted toward ileum smooth muscle spontaneous contractility. The observed calcium antagonistic effect was more potent in proximal colon than in ileum. The extract showed a noncompetitive reversible antagonism to carbachol, both in proximal colon and ileum, with a higher potency in proximal colon. The antimicrobial effects of AC extract were observed toward Campylobacter jejuni, Escherichia coli, and Salmonella spp., while Bifido and Lactobacillus were not affected by treatment. These effects, however, occurred at concentrations fivefold higher than those inhibiting ileum and colon contractility. In conclusion, our results suggest that AC affects intestinal contractility without affecting intestinal bacterial flora and this may result in clinical benefits in patients suffering from nonbacterial diarrhea.


Assuntos
Acacia/química , Diarreia/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Colo/efeitos dos fármacos , Colo/fisiopatologia , Diarreia/fisiopatologia , Feminino , Cobaias , Humanos , Íleo/efeitos dos fármacos , Íleo/fisiopatologia , Masculino , Contração Muscular/efeitos dos fármacos , Extratos Vegetais/química
19.
PLoS One ; 12(11): e0188567, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29190763

RESUMO

The high incidence of vulvo-vaginal candidiasis, combined with the growing problems about azole resistance and toxicity of antifungal drugs, highlights the need for the development of new effective strategies for the treatment of this condition. In this context, natural compounds represent promising alternatives. The cyanobacterium Spirulina platensis, a blue-green alga, exhibits antimicrobial activities against several microorganisms. Nevertheless, only few data about the antifungal properties of Spirulina platensis are available and its potential toxic effects have not been largely investigated. The aim of this study was to evaluate the in vitro activity of a fully-characterized water extract of Spirulina platensis against 22 strains of Candida spp. Prior to considering its potential topical use, we both investigated whether the extract exerted target activities on guinea pig uterine smooth muscle, and the impact of Spirulina platensis on the dominant microorganisms of the vaginal microbiota (i.e., lactobacilli), in order to exclude possible adverse events. By means of a broth microdilution assay, we found that the microalga extract possesses good antifungal properties (MIC: 0.125-0.5 mg/ml), against all the Candida species with a fungicidal activity. At the concentrations active against candida, Spirulina platensis did not modify the spontaneous basic waves pattern of uterine myometrium as underlined by the absence of aberrant contractions, and did not affect the main health-promoting bacteria of the vaginal ecosystem. Finally, we evaluated the selectivity index of our extract by testing its cytotoxicity on three different cell lines and it showed values ranging between 2 and 16. Further in vivo studies are needed, in particular to evaluate the use of control-release formulations in order to maintain Spirulina platensis concentrations at anti-Candida active doses but below the toxic levels found in the present work.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candidíase Vulvovaginal/microbiologia , Spirulina/química , Água/química , Animais , Candida/isolamento & purificação , Feminino , Cobaias , Humanos , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Microbiota , Contração Uterina/efeitos dos fármacos , Vagina/microbiologia
20.
J Med Chem ; 49(24): 7140-9, 2006 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-17125266

RESUMO

Our previous structure-affinity relationship study had considered the enantiomers of the naphthodioxane, tetrahydronaphthodioxane, and 2-methoxy-1-naphthoxy analogues (compounds 1, 3, and 2, respectively) of 2-(2,6-dimethoxyphenoxyethylaminomethyl)-1,4-benzodioxane, the well-known alpha1-adrenoceptor (alpha1-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for alpha1-AR subtypes and 5-HT1A receptor. Here, we extend investigations to antagonist activity enclosing new enantiomeric pairs, namely those of the methoxytetrahydronaphthoxy and methoxybiphenyloxy WB4101 analogues (4 and 5-7, respectively) and of a double-modified WB4101 derivative (8) resulting from hybridization between 2 and 3. We found that (S)-2 is a very potent (pA2 10.68) and moderately selective alpha1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 7.98) and highly selective alpha1A-AR antagonist. Both of these compounds and (S)-WB4101 seem to act as inverse agonists in a vascular model. The results, which generally validate the logic we followed in designing these eight compounds, are acceptably rationalized by comparative SAR analysis of binding and functional affinities.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Compostos de Bifenilo/síntese química , Dioxanos/síntese química , Metilaminas/síntese química , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/síntese química , Agonistas de Receptores Adrenérgicos alfa 1 , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Células CHO , Cricetinae , Cricetulus , Dioxanos/química , Dioxanos/farmacologia , Humanos , Técnicas In Vitro , Masculino , Metilaminas/química , Metilaminas/farmacologia , Especificidade de Órgãos , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/farmacologia
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