Cyclic AMP relaxation of rat aortic smooth muscle is mediated in part by decrease of depletion of intracellular Ca(2+) stores and inhibition of capacitative calcium entry.

Despite a large number of studies, the mechanism by which 3',5'-cyclic monophosphate (cAMP) induces vasorelaxation is not fully understood. The comparison between results obtained in different vessels or species has often been the source of conflicting reports. In order to shed more light onto this mechanism, we studied the effects of forskolin in phenylephrine-pre-contracted endothelium-denuded rat aorta and measured cAMP levels in rat aortic myocytes by enzyme-immunoassay.

Monoamino oxidase a: an interesting pharmacological target for the development of multi-target QSAR.

With the significant increase of life expectancy of populations in societies today, the importance of the discovery of drugs associated with neurodegenerative diseases has emerged. Therefore, neurodegenerative diseases are an important topic in Medicinal Chemistry. Although drug discovery is considered a complex and slow process, new approaches and methods have been developed with the intention of finding new chemical entities in more efficient ways.

Trans-resveratrol simultaneously increases cytoplasmic Ca(2+) levels and nitric oxide release in human endothelial cells.

Scope: The aim of this study was to investigate whether the dietary polyphenol trans-resveratrol (t-Resv) increases [Ca(2+)](c) in endothelial cells, leading to a simultaneous augmentation of nitric oxide (NO) biosynthesis.

Methods And Results: We have separately and simultaneously measured [Ca(2+)](c) and NO in human endothelial cells using the Ca(2+) indicator fura-2 and the NO-sensitive fluorescent probe 4,5-diaminofluorescein. In ∼30% of cells, t-Resv (30 μM) induced an increase in [Ca(2+)](c) with a transient as well as sustained component and a simultaneous increase in NO biosynthesis.

Homoisoflavonoids: natural scaffolds with potent and selective monoamine oxidase-B inhibition properties.

A series of homoisoflavonoids [(E)-3-benzylidenechroman-4-ones 1a-w, 3-benzyl-4H-chromen-4-ones 2a-g, and 3-benzylchroman-4-ones 3a-e] have been synthesized and tested in vitro as inhibitors of human monoamine oxidase isoforms A and B (hMAO-A and hMAO-B). Most of the compounds were found to be potent and selective MAO-B inhibitors. In general, the (E)-3-benzylidenechroman-4-ones 1a-w showed activities in the nano- or micromolar range coupled with high selectivity against hMAO-B.

Synthesis and biological evaluation of N-substituted-3,5-diphenyl-2-pyrazoline derivatives as cyclooxygenase (COX-2) inhibitors.

Eighteen new 1-N-substituted-3,5-diphenyl-2-pyrazoline derivatives have been synthesized and cyclooxygenase (COX-1 and COX-2) inhibitory activities have been evaluated. The results of these biological assays showed that all of new derivatives are not endowed with improved anti-inflammatory activity against COX-1, but some of them showed a good activity against COX-2. To evaluate the binding mode of the most significative compounds (2d, 2f, 2g and 2k) docking studies were carried out.

Synthesis and molecular modelling studies of prenylated pyrazolines as MAO-B inhibitors.

A series of N-substituted-3-[(2'-hydroxy-4'-prenyloxy)-phenyl]-5-phenyl-4,5-dihydro-(1H)-pyrazolines were synthesized and tested on human monoamine oxidase-A and -B isoforms. Structure-activity relationships and molecular modelling showed that some substitutions, such as benzyloxy or chlorine atom, improve the best interaction with active site of hMAO-B.

New pyridazinone derivatives with vasorelaxant and platelet antiaggregatory activities.

New 6-substituted and 2,6-disubstituted pyridazinone derivatives were obtained starting from easily accessible alkyl furans by using oxidation with singlet oxygen to give 4-methoxy or 4-hydroxybutenolides, key intermediates of this synthetic strategy. The new pyridazinone derivatives have been studied as vasorelaxant and antiplatelet agents. Analysis of biological data revealed the silyl ethers (4a-i) and N,O-dibenzyl derivatives (6g-i) as the most active compounds.

Synthesis, stereochemical separation, and biological evaluation of selective inhibitors of human MAO-B: 1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazines.

Novel 1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazine derivatives have been investigated for their ability to inhibit selectively the activity of the human B isoform of monoamine oxidase. These compounds were obtained as racemates and (R)-enantiomers by a stereoconservative synthetic pattern in high yield and enantiomeric excess. The (S)-enantiomers of the most active derivatives have been separated by enantioselective HPLC.

Blockade by nanomolar resveratrol of quantal catecholamine release in chromaffin cells.

The cardiovascular protecting effects of resveratrol, an antioxidant polyphenol present in grapes and wine, have been attributed to its vasorelaxing effects and to its anti-inflammatory, antioxidant, and antiplatelet actions. Inhibition of adrenal catecholamine release has also been recently implicated in its cardioprotecting effects. Here, we have studied the effects of nanomolar concentrations of resveratrol on quantal single-vesicle catecholamine release in isolated bovine adrenal chromaffin cells.

Investigations on the 2-thiazolylhydrazyne scaffold: synthesis and molecular modeling of selective human monoamine oxidase inhibitors.

A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71-99%) and characterized by elemental analysis and (1)H NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) inhibitory activity and selectivity and most of them showed IC(50) values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the CN, displayed IC(50)=3.

Synthesis, semipreparative HPLC separation, biological evaluation, and 3D-QSAR of hydrazothiazole derivatives as human monoamine oxidase B inhibitors.

The present study reports on synthesis in high yields (70-99%), HPLC enantioseparation, inhibitory activity against human monoamino oxidases, and molecular modeling including 3D-QSAR studies, of a large series of (4-aryl-thiazol-2-yl)hydrazones (1-45). Most of the synthesized compounds proved to be potent and selective inhibitors of hMAO-B isoform in the micromolar or nanomolar range, thus demonstrating that hydrazothiazole could be considered a good pharmacophore to design new hMAO-B inhibitors. Due to the presence in some derivatives of a chiral center, we also performed a semipreparative chromatographic enantioseparation of these compounds obtained by a stereoconservative pattern.

Antidepressant-like profile and MAO-A inhibitory activity of 4-propyl-2H-benzo[h]-chromen-2-one.

Aims: To evaluate the central nervous pharmacological profile of 4-propyl-2H-benzo[h]-chromen-2-one (FCS-304) in ICR mice and its monoamine oxidase inhibitor activity.

Main Methods: FCS-304 was evaluated in screening test of central nervous system in ICR mice and against MAO activity.

Key Findings: FCS-304 (25-200mg/Kg, p.

Chromone-2- and -3-carboxylic acids inhibit differently monoamine oxidases A and B.

Chromone carboxylic acids were evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. The biological data indicated that only chromone-3-carboxylic acid is a potent hMAO-B inhibitor, with a high degree of selectivity for hMAO-B compared to hMAO-A. Conversely the chromone-2-carboxylic acid resulted almost inactive against both MAO isoforms.

Synthesis and vasorelaxant and platelet antiaggregatory activities of a new series of 6-halo-3-phenylcoumarins.

A series of 6-halo-3-hydroxyphenylcoumarins (resveratrol-coumarins hybrid derivatives) was synthesized in good yields by a Perkin reaction followed by hydrolysis. The new compounds were evaluated for their vasorelaxant activity in intact rat aorta rings pre-contracted with phenylephrine (PE), as well as for their inhibitory effects on platelet aggregation induced by thrombin in washed human platelets. These compounds concentration-dependently relaxed vascular smooth muscle and some of them showed a platelet antiaggregatory activity that was up to thirty times higher than that shown by trans-resveratrol and some other previously synthesized derivatives.

A new series of flavones, thioflavones, and flavanones as selective monoamine oxidase-B inhibitors.

A new series of synthetic flavones, thioflavones, and flavanones has been synthesized and evaluated as potential inhibitors of monoamine oxidase isoforms (MAO-A and -B). The most active series is the flavanone one with higher selective inhibitory activity against MAO-B. Some of these flavanones (mainly the most effective) have been separated and tested as single enantiomers.

Synthesis and inhibitory activity against human monoamine oxidase of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives.

A series of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives has been synthesized and assayed for their ability to inhibit the activity of the A and B isoforms of human monoamine oxidase (hMAO). Some of these compounds were endowed with a selective inhibitory activity against hMAO-B in the micromolar range. The most active of the series is the compound 13, N1-thiocarbamoyl-3-(fur-2'-yl)-5-(4'-fluoro-phenyl)-4,5-dihydro-(1H)-pyrazole, with IC(50) 2.

Electrochemical synthesis and structural characterization of Co(II), Ni(II) and Cu(II) complexes of N,N-bis(4,5-dimethyl-2-hydroxybenzyl)-N-(2-pyridylmethyl)amine.

The electrochemical oxidation of anodic metal (cobalt, nickel or copper) in a cell containing an acetonitrile solution of the ligand N,N-bis(4,5-dimethyl-2-hydroxybenzyl)-N-(2-pyridylmethyl)amine (H2L) affords complexes [Co2L2].H2O (1), [Ni3L3] (2) and [Cu2L2] 3H2O (4). On using nickel as the anode and the addition to the solution electrolytic phase of the amount of water necessary to saturate the solution, the electrolytic process gave rise to the new compound [Ni2L2(H2O)1.

Resveratrol induces mitochondrial alterations, autophagy and a cryptobiosis-like state in scuticociliates.

The phytoalexin resveratrol (RESV), a defensive substance produced by plants in response to infection by pathogenic microorganisms, displays a wide range of biological effects in mammalian cells. In the present study, we analysed the in vitro effect of RESV on the amphizoic ciliate Philasterides dicentrarchi and demonstrated for the first time that this polyphenol causes cellular and metabolic abnormalities that generate an autophagic process and a state similar to cryptobiosis in the ciliate. At concentrations between 50 and 100 microM, RESV had a cytocidal effect when the ciliate was grown in medium with low levels of nutrients, and a cytostatic effect when the parasite was grown in culture media rich in nutrients.

Synthesis and evaluation of 6-methyl-3-phenylcoumarins as potent and selective MAO-B inhibitors.

A series of 6-methyl-3-phenylcoumarins 3-6 were synthesized and evaluated as monoamine oxidase A and B (MAO-A and MAO-B) inhibitors. A comparative study between the three possible mono methoxy 3-phenyl derivatives and the p-hydroxy analogue is reported. The synthesis of these new resveratrol-coumarin hybrids was carried out by a Perkin reaction between the 5-methylsalicylaldehyde and the corresponding phenylacetic acids.

A new series of 3-phenylcoumarins as potent and selective MAO-B inhibitors.

6-Methyl-3-phenylcoumarins 3-6 were designed, synthesized and evaluated as monoamine oxidase A and B (MAO-A and MAO-B) inhibitors. The synthesis of these new compounds (resveratrol-coumarin hybrids) was carried out with good yield by a Perkin reaction, from the 5-methylsalicylaldehyde and the corresponding phenylacetic acid. They show high selectivity to the MAO-B isoenzyme, with IC(50) values in the nanomolar range.

Chalcones: a valid scaffold for monoamine oxidases inhibitors.

A large series of substituted chalcones have been synthesized and tested in vitro for their ability to inhibit human monoamine oxidases A and B (hMAO-A and hMAO-B). While all the compounds showed hMAO-B selective activity in the micro- and nanomolar ranges, the best results were obtained in the presence of chlorine and hydroxyl or methoxyl substituents. To better understand the enzyme-inhibitor interaction and to explain the selectivity of the most active compounds toward hMAO-B, molecular modeling studies were carried out on new, high resolution, hMAO-B crystallographic structures.

Alignment-free prediction of a drug-target complex network based on parameters of drug connectivity and protein sequence of receptors.

There are many drugs described with very different affinity to a large number of receptors. In this work, we selected drug-receptor pairs (DRPs) of affinity/nonaffinity drugs to similar/dissimilar receptors and we represented them as a large network, which may be used to identify drugs that can act on a receptor. Computational chemistry prediction of the biological activity based on quantitative structure-activity relationships (QSAR) substantially increases the potentialities of this kind of networks avoiding time- and resource-consuming experiments.

Synthesis, molecular modeling, and selective inhibitory activity against human monoamine oxidases of 3-carboxamido-7-substituted coumarins.

A large series of 3-carboxamido-7-substituted coumarins have been synthesized and tested in vitro for their human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitory activity. Taking into account all the relevant structural information on MAOs reported in the literature, we made some changes in the coumarin nucleus and examined with particular attention the effect on activity and selectivity of substituting at position 3 with N-aryl or N-alkyl carboxamide and at position 7 with a benzyloxy or a 4'-F-benzyloxy group. Some of the assayed compounds proved to be potent, selective inhibitors of hMAO-B with IC(50) values in the micromolar range.