References of "Chavatte, Philippe"
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See detailMolecular modeling of phthalates – PPARs interactions
Kambia, Nicolas; Renault, Nicolas; Dilly, Sébastien ULg et al

in Journal of Enzyme Inhibition & Medicinal Chemistry (2008), 23(5), 611-616

Di(2-ethylhexyl) phthalate (DEHP) is the most widely plasticizer for polyvinyl chloride (PVC) that is used in plastic tubes, in medical and paramedical devices as well as in food storage packaging. The ... [more ▼]

Di(2-ethylhexyl) phthalate (DEHP) is the most widely plasticizer for polyvinyl chloride (PVC) that is used in plastic tubes, in medical and paramedical devices as well as in food storage packaging. The toxicological profile of DEHP has been evaluated in a number of experimental animal models and has been extensively documented. Its toxicity is in part linked to the activation of the peroxisome proliferator-activated receptor a (PPARa). As a response, an intensive research for a new, biologically inert plasticizer has been initiated. Among the alternative studied, tri(2-ethylhexyl) trimellitate (TEHTM) or trioctyl trimellitate (TOTM) has attracted increasing interest. However, very little information is available on their biological effects. We proceeded to dock TOTM, DEHP and its metabolites in order to identify compounds that are likely to interact with PPARa and PPARg binding sites. The results obtained hint that TOTM is not able to bind to PPARs and should therefore be safer than DEHP. [less ▲]

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See detailHomology modeling of MT(1) and MT(2) receptors
Farce, Amaury; Chugunov, Anton O.; Logé, Cédric et al

in European Journal of Medicinal Chemistry (2008), 43

Melatonin is a neurohormone synthesized and secreted mainly during the dark period of the circadian cycle by the pineal gland. It has already been proved to be involved in a number of chronobiological ... [more ▼]

Melatonin is a neurohormone synthesized and secreted mainly during the dark period of the circadian cycle by the pineal gland. It has already been proved to be involved in a number of chronobiological processes, most of them being mediated by its membranar receptors MT1 and MT2. Both are members of the GPCR class and, despite the interest they elicit, their 3D structure is still to be described. Models for both human MT1 and MT2 receptors have been constructed by homology modeling, using the X-ray structure of bovine rhodopsin as template. These models have been evaluated in terms of hydrophobic properties of the helices and refined to take into account the rearrangement of GPCRs necessary for their activation, thus leading to a putative activated model for each subtype. [less ▲]

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See detailMolecular modelling study of bis-isoquinolinium derivatives as small conductance Ca2+ - activated K+ channel blockers
Dilly, Sébastien ULg; Graulich, Amaury; Chavatte, Philippe et al

Poster (2008, May 30)

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system and the periphery. Three subtypes of SK channels have been identified so far in ... [more ▼]

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system and the periphery. Three subtypes of SK channels have been identified so far in different parts of the brain. Activation of SK channels by a rise in intracellular calcium leads to the hyperpolarisation of the membrane, hence reducing cell excitability. Blocking the SK channels might be beneficial for the treatment of depression, Parkinson’s disease and cognitive disorders. In this context, starting from the scaffold of N-methyl-laudanosine (NML) which is a known SK channel blocker (Scuvée-Moreau et al., 2002), a series of original bis-isoquinolinium derivatives were synthezised and evaluated for their affinity on the apamin-sensitive sites (Graulich et al., 2007). These quaternary compounds are powerful blockers, and the most active ones have 10 times more affinity for SK channels than dequalinium. Based on a conformational analysis, a molecular modeling study was also performed. The heads of the various conformational families were compared to a pharmacophoric model previously described (Dilly et al., 2005). The in silico results are well correlated by the in vitro binding studies. Firstly, a 6,7-dimethoxy or a 6,7,8-trimethoxy substitution is shown to be favourable. Secondly, although the length of the linker has no significant influence in the alkane derivatives, the ortho and meta linkers lead to more favourable conformations than the para linker in the xylene derivatives. [less ▲]

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See detailBis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca2+-activated K+ channel blockers
Graulich, Amaury ULg; Lamy, Cédric ULg; Alleva, Livia ULg et al

in Bioorganic & Medicinal Chemistry Letters (2008), 18(11), 3440-3445

So far, small conductance Ca2+-activated K+ channel (SK) blockers mostly consist of quaternary ammonium derivatives or peptides. Due to their physicochemical properties, these blockers are not suitable to ... [more ▼]

So far, small conductance Ca2+-activated K+ channel (SK) blockers mostly consist of quaternary ammonium derivatives or peptides. Due to their physicochemical properties, these blockers are not suitable to study the physiological roles of SK channels in the central nervous system in vivo. Herein, we report the discovery of a chiral bis-tertiary amine with SK blocking properties from chemical modulation of laudanosine. AG525E1 has an affinity for SK channels (K-i = 293 nM) approximately 100-fold higher than the tertiary compound laudanosine (K-i similar to 30 mu M) and similar to the charged compound dequalinium (K-i = 221 nM). AG525E1 equipotently blocks SK1, SK2 and SK3 currents in transfected cell lines. Because of its basic and lipophilic properties, it can reach central SK targets. (c) 2008 Elsevier Ltd. All rights reserved. [less ▲]

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See detailSynthesis and Radioligand Binding Studies of Bis-Isoquinolinium Derivatives as Small Conductance Ca(2+)-Activated K(+) Channel Blockers
Graulich, Amaury ULg; Dilly, Sébastien ULg; Farce, Amaury et al

in Journal of Medicinal Chemistry (2007), 50(21), 5070-5075

Starting from the scaffold of N-methyllaudanosine and N-methylnoscapine, which are known small conductance Ca2+-activated K+ channel blockers, original bis-isoquinolinium derivatives were synthezised and ... [more ▼]

Starting from the scaffold of N-methyllaudanosine and N-methylnoscapine, which are known small conductance Ca2+-activated K+ channel blockers, original bis-isoquinolinium derivatives were synthezised and evaluated using binding studies, electrophysiology, and molecular modeling. These quaternary compounds are powerful blockers, and the most active ones have 10 times more affinity for the channels than dequalinium. The unsubstituted compounds possess a weaker affinity than the analogues having a 6,7-dimethoxy- or a 6,7,8-trimethoxy substitution. The length of the linker has no influence in the alkane derivatives. In relation to the xylene derivatives, the affinities are higher for the ortho and meta isomers. These results are well corroborated by a molecular modeling study. Finally, the most effective compounds have been tested in electrophysiological experiments on midbrain dopaminergic neurons and demonstrate the blocking potential of the apamin-sensitive after-hyperpolarization. [less ▲]

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See detailQuantitative Structure-Activity Relatioships studies of antioxydant hexahydropyridoindoles and flavonoids derivatives
Durand, Anne-Catherine; Farce, Amaury; Carato, Pascal et al

in Journal of Enzyme Inhibition & Medicinal Chemistry (2007), 22(5), 556-562

In order to predict the antioxidant activity of 22 pinoline derivatives (1,2,3,4-tetrahydro-b-carbolines), two dimensional quantitative-structure activity relationships (2D-QSAR) analysis of 19 ... [more ▼]

In order to predict the antioxidant activity of 22 pinoline derivatives (1,2,3,4-tetrahydro-b-carbolines), two dimensional quantitative-structure activity relationships (2D-QSAR) analysis of 19 hexahydropiridoindoles and 12 flavonoids was realized. Five statistically significant models were obtained from randomly constituted training sets (21 compounds) and subsquently validated with the corresponding test sets (10 compounds). Antioxidant activity (pIC50) was correlated with 5 molecular descriptors calculated with the software DRAGON. The best predictive model (n = 21, q2 = 0.794, N = 2, r2 = 0.888, s = 0.157) could offer structural insights into the features conferring a strong antioxidant activity to compounds built from a pinoline scaffold prior to their synthesis. [less ▲]

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See detailThree-dimensional quantitative structure-activity relationship of MT3 melatonin binding site ligands: a comparative molecular field analysis
Farce, Amaury; Dilly, Sébastien ULg; Sabaouni, Ahmed et al

in QSAR & Combinatorial Science (2007), 26(7), 820-827

The Three-Dimensional Quantitative Structure –Activity Relationship (3D-QSAR) approach using Comparative Molecular Field Analysis (CoMFA) was applied to a series of 39 compounds evaluated as MT3 binding ... [more ▼]

The Three-Dimensional Quantitative Structure –Activity Relationship (3D-QSAR) approach using Comparative Molecular Field Analysis (CoMFA) was applied to a series of 39 compounds evaluated as MT3 binding site ligands. The X-ray crystal structure of MT3/quinone reductase 2 was used to obtain the putative bioactive conformation of these ligands. Five statistically significant models were obtained from the randomly constituted training sets (30 compounds) and subsequently validated with the corresponding test sets (nine compounds). The best predictive model (n=30, q2=0.608, N=3, r2=0.897, s=0.288, F=75.4) can predict inhibitory activity for a wide range of compounds and offers important structural insight into designing MT3 ligands prior to their synthesis. [less ▲]

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See detailConstruction d’un modèle du récepteur sérotoninergique 5HT2c
Dilly, Sébastien ULg; Farce, Amaury; Yous, Said et al

Poster (2006, September 27)

La 5-hydroxytryptamine, plus couramment appelée sérotonine, a été découverte indépendamment en 1937 dans le tractus gastro-intestinal, et en 1948 dans le sérum, puis trouvée également dans le cerveau en ... [more ▼]

La 5-hydroxytryptamine, plus couramment appelée sérotonine, a été découverte indépendamment en 1937 dans le tractus gastro-intestinal, et en 1948 dans le sérum, puis trouvée également dans le cerveau en 1953. Sa structure a pour sa part été déterminée en 1949. Cette découverte a été initialement basée sur ses propriétés contractantes sur les muscles lisses. Le système sérotoninergique est cependant beaucoup plus important que ces premières investigations ne le laissaient envisager, puisqu’il intervient pratiquement dans toutes les réponses physiologiques, tant au niveau périphérique, où la sérotonine est impliquée dans l’hypertension, l’asthme ou l’acidité gastrique, qu’au niveau central, où elle joue un rôle majeur dans la régulation de l’humeur. Cette capacité lui donne une grande importance dans le traitement des dépressions. C’est dans ce cadre que se placent nos travaux, portant plus particulièrement sur une nouvelle classe thérapeutique dont le chef de file est l’agomélatine. Cette dernière agit selon un mode d’action original en se fixant à la fois aux récepteurs mélatoninergiques et au récepteur sérotoninergique 5HT2c, ce qui a donné naissance au concept MASSA (Melatonin Agonist and Selective Serotonin Antagonist). Comme la plupart des récepteurs sérotoninergiques, le sous-type 5HT2c est un Récepteur à sept domaines transmembranaires Couplé à une Protéine G (RCPG). La structure tridimensionnelle de 5HT2c n’est pas connue expérimentalement, et nous avons donc fait appel à la modélisation par homologie comparative pour construire un modèle nous permettant d’étudier ses interactions avec l’agomélatine. [less ▲]

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See detailHomology modeling of the serotoninergic 5-HT2c receptor
Farce, Amaury; Dilly, Sébastien ULg; Yous, Said et al

in Journal of Enzyme Inhibition and Medicinal Chemistry (2006), 21

Since its discovery, 5-hydroxytryptamine, more usually called serotonin, has been an elusive candidate as a major mood regulator. This capacity gives it a great importance in the treatment of depression ... [more ▼]

Since its discovery, 5-hydroxytryptamine, more usually called serotonin, has been an elusive candidate as a major mood regulator. This capacity gives it a great importance in the treatment of depression. It is within this framework that our work takes place, as it is related more particularly to a new therapeutic class whose leader is agomelatine. This compound binds to the melatoninergic receptors and to the serotoninergic 5-HT2c receptor, giving rise to the MASSA concept (Melatonin Agonist and Selective Serotonin Antagonist). Like the majority of the serotoninergic receptors, the sub-type 5-HT2c is a G-protein coupled receptor (GPCR). The three-dimensional structure of 5-HT2c is not experimentally known, and we thus resorted to comparative homology modelling to build a model allowing us to study its interactions with agomelatine. [less ▲]

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See detailIdentification of a pharmacophore of SKCa channel blockers
Dilly, Sébastien ULg; Graulich, Amaury ULg; Farce, Amaury et al

in Journal of Enzyme Inhibition and Medicinal Chemistry (2005), 20(6), 517-523

Small conductance calcium-activated potassium channels ( SK) are widely expressed throughout the central nervous system ( CNS) and the periphery. Three subtypes of SK channels have so far been identified ... [more ▼]

Small conductance calcium-activated potassium channels ( SK) are widely expressed throughout the central nervous system ( CNS) and the periphery. Three subtypes of SK channels have so far been identified in different parts of the brain. Activation of the SK channels by a rise in intracellular calcium leads to the hyperpolarisation of the membrane, reducing cell excitability. Blocking the SK channels might be beneficial in the treatment of depression, Parkinson's disease and cognitive disorders. However, few blockers of SK channels have been characterized. In this study, a pharmacophoric model of SK channels blockers is presented. It is based on a series of nonpeptidic compounds and apamin, a peptidic blocker. To create the pharmacophore model, the conformational space of nonpeptidic blockers was investigated to generate a series of distance constraints applied to a simulated annealing study of apamin. The resulting conformation was superimposed with the nonpeptidic blockers to give a pharmacophore. [less ▲]

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See detailRecherche d’un pharmacophore de ligands de canaux SK par Modélisation Moléculaire
Dilly, Sébastien ULg; Graulich, Amaury; Farce, Amaury et al

Conference (2005, January 28)

Parmi les canaux ioniques impliqués dans le contrôle de l'activité neuronale, les canaux potassiques calcium-dépendants de basse conductance, dénommés canaux SK, constituent une cible thérapeutique ... [more ▼]

Parmi les canaux ioniques impliqués dans le contrôle de l'activité neuronale, les canaux potassiques calcium-dépendants de basse conductance, dénommés canaux SK, constituent une cible thérapeutique intéressante. En effet, ils sous-tendent la posthyperpolarisation ("AfterHyperPolarization") de durée moyenne (mAHP) qui limite l'excitabilité de divers types de neurones du système nerveux central (SNC). Leur blocage pourrait être ainsi bénéfique dans le traitement de divers troubles du SNC comme la maladie de Parkinson, la dépression ou encore les désordres cognitifs. Jusqu'à présent, le bloqueur de référence des canaux SK est l’apamine, un octadécapeptide issu du venin d'abeille. En revanche, peu de composés synthétiques avec une affinité proche de celle de l’apamine ont été caractérisés. Dans ce contexte, nous avons développé un modèle pharmacophorique de bloqueurs non-sélectifs qui a révélé, entre autres, une distance optimale de 5.6 Å entre deux charges positives. Ce modèle sera le point de départ de futures investigations dans le développement de nouveaux bloqueurs des canaux SK. [less ▲]

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See detailAntioxydant activity of β-carboline derivatives in the LDL oxidation model
Hadjaz, Fariza; Besret, Soizic; Martin-Nizard, Françoise et al

in European Journal of Medicinal Chemistry (2001), 46

A series of b-carboline compounds were synthesized, starting from compound GWC22, their antioxidant activity was determined by inhibition of lipid peroxidation. The oxidation of LDL was induced in the ... [more ▼]

A series of b-carboline compounds were synthesized, starting from compound GWC22, their antioxidant activity was determined by inhibition of lipid peroxidation. The oxidation of LDL was induced in the presence of CuSO4 or 2,20-azobis(2-amidinopropane) dihydrochloride (AAPH). The protective actions of these compounds against the cytotoxicity were evaluated with lactate dehydrogenase (LDH) activity in bovine aortic endothelial cells (BAECs) and cellular vitality by measuring mitochondrial activity in the presence of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Most of compounds showed an higher antioxidant activity than GWC22 derivative (R = 1.6 for 5 mM CuSO4). The best antioxidant activities are phenolic and benzyloxy derivatives with ratio R = 1.9 to 2.8 for 1 mM CuSO4. These substances have protective actions and increase significantly the cell viability. [less ▲]

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