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See detailThe 5-HT1A agonism potential of substituted-piperazine-ethyl-amide derivatives is conserved in the hexyl homologues: molecular modeling and pharmacological evaluation
Dilly, Sébastien ULg; Scuvée-Moreau, Jacqueline ULg; Wouters, Johan et al

in Journal of Chemical Information & Modeling (2011), 51(11), 2961-2966

In a series of carboxamide and sulphonamide alkyl (ethyl to hexyl) piperazine analogues, although the size of the linker is very different, ethyl and hexyl derivatives possess a high affinity for 5-HT1A ... [more ▼]

In a series of carboxamide and sulphonamide alkyl (ethyl to hexyl) piperazine analogues, although the size of the linker is very different, ethyl and hexyl derivatives possess a high affinity for 5-HT1A receptors. Docking studies clearly show that hexyl and ethyl compounds favourably interact with the binding site of the active conformation of 5-HT1A receptors, thus confirming a possible agonist profile. This activity is effectively detected in electrophysiological experiments in which all four compounds inhibit the activity of rat dorsal raphe serotonergic neurons. [less ▲]

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See detailModulation of the 6-position of benzopyran derivatives and inhibitory effects on the insulin releasing process
Florence, Xavier; Dilly, Sébastien ULg; De Tullio, Pascal ULg et al

in Bioorganic & Medicinal Chemistry (2011)

The synthesis of different series of 4- and 6-substituted R/S-3,4-dihydro-2,2-dimethyl-2H-1- benzopyrans is described. All of these new benzopyran derivatives were bearing, at the 4- position, a ... [more ▼]

The synthesis of different series of 4- and 6-substituted R/S-3,4-dihydro-2,2-dimethyl-2H-1- benzopyrans is described. All of these new benzopyran derivatives were bearing, at the 4- position, a phenylthiourea moiety substituted on the phenyl ring by a meta or a para-electronwithdrawing group such as Cl or CN. The study aimed at exploring the influence of the nature of the substituent at the 6-position in order to develop new benzopyran-type KATP channel activators exhibiting an improved selectivity towards the insulin secreting cells. The original compounds were examined in vitro on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (vasorelaxant effect) and their activity was compared to that of the reference KATP channel activators (±)-cromakalim, (±)-pinacidil, diazoxide and to previously synthesized cromakalim analogues. Structure–activity relationships indicated that the inhibitory effect on the insulin secreting cells was related to the lipophilicity of the molecules and to the size of the substituent located at the 6-position. A marked inhibitory activity on the insulin secretory process was obtained with molecules bearing a bulky tertbutyloxycarbonylamino group at the 6-position (20-23). The latter compounds were found to have the same efficacy on the pancreatic endocrine tissue than some previously described molecules. Lastly, radioisotopic experiments further identified R/S-N-4-chlorophenyl-N’-(6- tert-butyloxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)thiourea (23) as a KATP channel opener. [less ▲]

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See detailInteraction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study
Dilly, Sébastien ULg; Liégeois, Jean-François ULg

in Journal of Computer-Aided Molecular Design (2011), 25(2), 163-169

The interaction of diazepine analogues like clozapine or olanzapine with D2 receptor was greatly affected by a mixture of HRP/H2O2 known to induce the formation of nitrenium ion. Unlike diazepine ... [more ▼]

The interaction of diazepine analogues like clozapine or olanzapine with D2 receptor was greatly affected by a mixture of HRP/H2O2 known to induce the formation of nitrenium ion. Unlike diazepine derivatives, the oxidative mixture had low impact on the affinity of oxa- and thiazepine derivatives such as loxapine, clothiapine or JL13 for the D2 receptor. Molecular docking simulations revealed a huge difference between the mode of interaction of clozapine nitrenium ion and the parent drug. Electronic and geometric changes of the tricyclic ring system caused by the oxidation appeared to prevent the compound finding the correct binding mode and could therefore explain the difference observed in binding affinities. [less ▲]

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See detailBinding properties of clozapine and related compounds on native D2 dopamine receptors in normal and oxidative medium
Liégeois, Jean-François ULg; Dilly, Sébastien ULg

Poster (2010, November 16)

Despite the presence of several side effects, clozapine remains a valuable drug in treating schizophrenia. The presence of haematological toxicity was proposed to be related to the formation of nitrenium ... [more ▼]

Despite the presence of several side effects, clozapine remains a valuable drug in treating schizophrenia. The presence of haematological toxicity was proposed to be related to the formation of nitrenium species (1). Indeed, nitrogen derivatives like clozapine or olanzapine are very sensitive to oxidation while oxygen or sulphur isosteres such as loxapine, clothiapine and JL13, possess a very low sensitivity to oxidation (2-4). In the present study, we explore the impact of oxidation conditions on the binding of these drugs on native rat dopamine D2 receptors. Rats brains were quickly removed after cerebral dislocation and dissected on ice to get striata. After weighting, tissues were homogenized in buffer and washed three times by centrifugation. The final pellet was dispersed in the appropriate volume of incubation buffer (Tris 50 mM, MgCl2 5 mM, EDTA (Na2) 1 mM buffered at pH 7.4 with 4N HCl) depending on the experimental conditions. In oxidative conditions, horseradish peroxidase (1.25 µg/tube) and H2O2 (50 µM) were added to the incubation buffer. [3H]-Spiperone was used as radioligand and the non specific binding was determined in the presence of haloperidol (10 µM). Incubation temperature and time were 27°C and 60 min respectively. Competition experiments were done with different molecules such as haloperidol and various tricyclic derivatives. In our previous studies (2,3), we had observed that compounds like clozapine or olanzapine are significantly affected by oxidative conditions. In the present report, we show that this sensitivity is also associated with a dramatic decrease of binding affinity. Unlike such diazepine analogues, the binding of loxapine and JL13, two oxygen isosteres is slightly affected in oxidative conditions. Firstly, these results show that the distal nitrogen is not affected by the oxidative conditions. Secondly, the nitrenium formation (1) might lead to a tridimensional change that would reduce the interactions in the binding pocket. The oxidative effect of HRP/H2O2 mixture can be prevented by addition of ascorbic acid to the incubation medium. Thus depending on the oxidant character of the extracellular medium in physiological or pathophysiological conditions, interaction of molecules with different targets can be modified significantly. [less ▲]

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See detailBlock of SK channels by the sigma agonist 1,3-di-o-tolyl-guanidine: evidence for a novel site of action for SK blockers
Dilly, Sébastien ULg; Lamy, Cédric; Snyders, Dirk et al

Poster (2010, October 16)

Among ion channels involved in the control of neuronal activity, small conductance calcium-activated potassium channels (SK) represent an interesting therapeutic target. Indeed, they underlie medium ... [more ▼]

Among ion channels involved in the control of neuronal activity, small conductance calcium-activated potassium channels (SK) represent an interesting therapeutic target. Indeed, they underlie medium duration afterhyperpolarizations (mAHPs) in many types of neurons, thus inhibiting cell excitability. Three subtypes of SK subunits, SK1, SK2 and SK3, have been cloned and are expressed differentially within the central nervous system (CNS). Blocking SK channels might be beneficial in the treatment of several CNS disorders such as depression (SK3), Parkinson’s disease (SK3) and cognitive disorders (SK2). So far, the prototypical blocker of SK channels is apamin, an octadecapeptide from bee venom. We have recently shown that apamin blocks SK channels by binding to a site distinct from that used by classical pore blockers such as tetraethylammonium (TEA) (Lamy et al. J. Biol. Chem. 2010, 285, 27067-77). We have also demonstrated that the nonpeptide blocker N-methyl-laudanosine (NML) (Scuvée-Moreau et al. J. Pharmacol. Exp. Ther. 2002, 302, 1176-83) competes for the binding site of the toxin. Further, our research team has recently shown that the sigma agonist 1,3-di-o-tolyl-guanidine (DTG) directly blocks SK currents in a voltage-independent manner (Lamy et al. Eur. J. Pharmacol. 2010, 641, 23-8). We have combined patch clamp experiments on cell lines with molecular modelling and mutagenesis, to try to identify the site where DTG blocks. DTG was found to be equipotent on wild-type (WT) and apamin-insensitive (e.g. SK2H337N) channels. Moreover, mutated channels with increased sensitivity to TEA (SK3V520F: mean IC50 of TEA: 0.34 mM versus 11 mM for WT channels) were blocked by DTG with the same potency as WT channels. Thus, DTG does not seem to share the site of either apamin or TEA. Modelling data were in agreement with this possibility because of the identification of various potential binding sites. Although preliminary, these results suggest the existence of yet another binding site in the outer pore region of SK channels. [less ▲]

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See detailEtude du mode de liaison des canaux potassiques de type SK et l’apamine par modélisation moléculaire
Dilly, Sébastien ULg; Lamy, Cédric; Seutin, Vincent ULg et al

Poster (2010, May 20)

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). A ce jour, 3 types de sous-unités, SK1, SK2 et SK3, ont été identifiés dans différentes régions du cerveau. Le blocage sélectif de ces canaux pourrait être bénéfique dans le traitement de divers troubles du SNC comme la maladie de Parkinson (SK3), la dépression (SK3) ou encore les désordres cognitifs (SK2) (Liégeois et al., 2003 ; Pedarzani et al., 2008). Jusqu’à présent, le site d’interaction entre les canaux SK et leurs bloqueurs n’a pas encore été précisément élucidé. Dans ce contexte, nous avons entrepris la modélisation de ces canaux par homologie comparative en se basant sur la structure cristalline du canal potassique KCSA (Doyle et al., 1998). La construction de ces canaux constitue la première étape dans la détermination des requis structuraux essentiels à l’affinité de bloqueurs et à la compréhension des modes de liaison de ces ligands. Le mode de liaison de l’apamine, bloqueur peptidique issu du venin d’abeille, a été ensuite exploré par « docking ». Afin de confirmer ce site de liaison potentiel, des expériences de mutagénèse dirigée ont été réalisées. Les premiers canaux mutants testés dans des expériences électrophysiologiques par la technique de « patch clamp » ont permis de valider certaines données théoriques. Grâce à cette stratégie, nous espérons préciser le mécanisme d'action des bloqueurs des canaux SK et, idéalement, découvrir des pistes pour concevoir des bloqueurs sélectifs. [less ▲]

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See detailMolecular modeling study of 4-phenylpiperazine and 4-phenyl-1,2,3,6-tetrahydropyridine derivatives: A new step towards the design of high-affinity 5-HT1A ligands
Dilly, Sébastien ULg; Graulich, Amaury; Liégeois, Jean-François ULg

in Bioorganic & Medicinal Chemistry Letters (2010), 20(2), 1118-1123

The main feature of many drugs having a 5-HT1A affinity is the presence of an arylpiperazine moiety. Indeed, the protonated nitrogen and the aromatic ring of the arylpiperazine compounds are considered ... [more ▼]

The main feature of many drugs having a 5-HT1A affinity is the presence of an arylpiperazine moiety. Indeed, the protonated nitrogen and the aromatic ring of the arylpiperazine compounds are considered crucial for the interaction with the receptor. However, the replacement of the piperazine moiety by a 1,2,3,6-tetrahydropyridine ring in 4-arylpiperazine-ethyl carboxamide derivatives was recently shown to be highly favourable for 5-HT1A affinity. In order to better understand the favourable effect of this chemical modification, we performed a conformational analysis of these compounds mainly based on the position of the phenyl ring relative to the piperazine and tetrahydropyridine moiety. In the piperazine compounds, the phenyl ring preferentially adopts a perpendicular orientation, whereas an almost planar orientation seems to be the most favourable conformation for the tetrahydropyridine compounds. Therefore, this conformational difference appears as a key for a better interaction with the receptor binding site. This result will serve for the designing high-affinity 5-HT1A ligands. [less ▲]

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See detailCombined experimental and computational approaches to study the action of blockers of small conductance calcium-activated potassium (SK) channels
Dilly, Sébastien ULg; Lamy, Cédric; Liégeois, Jean-François ULg et al

in Acta Physiologica Scandinavica (2010), 199(supplement 678), -10

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system (CNS) and underlie medium duration afterhyperpolarizations in many types of neurons ... [more ▼]

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system (CNS) and underlie medium duration afterhyperpolarizations in many types of neurons. Three subtypes of SK channels, SK1, SK2 and SK3, have been identified so far in different parts of the brain. Blocking SK channels might be beneficial in the treatment of several CNS disorders such as depression, Parkinson’s disease and cognitive disorders. Until now, the precise site of interaction between these channels and their blockers has not yet been elucidated. In this context, molecular modeling is a theoretical approach that can quickly provide ideas on the binding mode of SK blockers. We first performed homology modeling of the S5-H5-S6 portion of the channels on the basis of the crystal structure of the KcsA potassium channel (Zhou et al. Nature. 2001, 414, 43-48). The binding sites of N-methyl-laudanosine (NML) (Scuvée-Moreau et al. J. Pharmacol. Exp. Ther. 2002, 302, 1176-83), a non-selective and non-peptidic ligand, and apamin (Blatz et al. Nature. 1986, 323, 718-20), an octadecapeptide with a preference for the SK2 subtype, were subsequently explored by docking analysis. Different amino-acids were suggested to interact with the two blockers. The docking of NML revealed a binding site in the turret region, far from the pore. The docking of apamin identified a very large binding site that includes a portion of the site of NML. In order to confirm the predicted binding sites, site-directed mutagenesis was used. The first mutant channels tested in electrophysiological experiments by the patch clamp technique validated some of the theoretical data. Using this strategy, we hope to get a better understanding of the mechanism of action of SK blockers and eventually find strategies to obtain subtype-selective blockers. [less ▲]

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See detailConformational analysis of new 5-HT1A ligands by molecular modeling
Dilly, Sébastien ULg; Graulich, Amaury; Liégeois, Jean-François ULg

Conference (2009, May 14)

5-HT1A receptors represent a major target for research and drug development due to their involvement in pathologies such as anxiety,1 depression,2 sleep and memory disorders,3,4 and schizophrenia.5 The ... [more ▼]

5-HT1A receptors represent a major target for research and drug development due to their involvement in pathologies such as anxiety,1 depression,2 sleep and memory disorders,3,4 and schizophrenia.5 The main feature of many drugs having a 5-HT1A affinity is the presence of arylpiperazine moiety.6 Indeed, the protonated nitrogen and the aromatic ring of the arylpiperazine compounds are considered crucial for the interaction with the receptor.7 Interestingly, an in vitro binding study realized in our laboratory reveals the presence of the 1,2,3,6-tetrahydropyridine instead of the piperazine moiety in 4-arylpiperazine-ethyl carboxamide derivatives is highly favourable for 5-HT1A affinity. In order to better understand the favourable effect of this chemical modification, we have performed a conformational analysis of these compounds mainly based on the position of the phenyl ring relative to the piperazine and tetrahydropyridine ones. In the piperazine compounds, the phenyl ring is found in a perpendicular orientation, whereas an almost planar orientation seems to be the most favourable conformation for the tetrahydropyridine compounds (See figure). Therefore, the almost planar orientation of the 4-substituted phenyl ring appears as an important spatial requirement for an optimal interaction with the receptor binding site. This finding could lead to new ideas in the design of high-affinity 5-HT1A ligands. [less ▲]

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See detailDirect block of SK2 and SK3 current by the sigma agonist 1,3-di-(2-tolyl)guanidine
Lamy, Cédric; Moreau, Jacqueline ULg; Dilly, Sébastien ULg et al

Poster (2008, November 17)

Sigma receptors are widely distributed in the central nervous system where they modulate neurotransmitter release, receptor function, ionic channel activity and calcium homeostasis. Two subtypes of sigma ... [more ▼]

Sigma receptors are widely distributed in the central nervous system where they modulate neurotransmitter release, receptor function, ionic channel activity and calcium homeostasis. Two subtypes of sigma receptors have been identified (sigma-1 and sigma-2) with different pharmacological profiles, anatomical distribution and physiological functions. 1,3-Di-(2-tolyl)guanidine (DTG) is a sigma-1 and sigma-2 agonist which is widely used to probe the function of these receptors. It has recently been shown that sigma-1 receptor activation reduces the opening of SK channels in the hippocampus. We have observed that DTG (100 µM) reduces the apamin-sensitive afterhyperpolarization (AHP) of dopaminergic neurons within a slice preparation by ~60%, an effect not observed with other sigma agonists. In addition, neither the selective sigma-1 antagonist BD 1047 (30 µM) nor haloperidol (1 µM) blocked the effect of DTG, which suggested that the inhibition of the AHP might result from a direct block of the underlying SK channels. Whole-cell recordings were made from HEK293 cells transiently transfected with rSK2 or hSK3 cDNA in symmetrical K+ conditions with currents activated by a [Cai] of 1 µM. Expressed SK2 and SK3 channels displayed a classical pharmacology, being blocked by apamin with mean IC50’s of 100 pM and 4 nM, respectively. In contrast, both channel subtypes were blocked with equal sensitivity by N-methyl-laudanosine (NML). DTG inhibited both SK2 and SK3 currents with the same potency (IC50’s were ~30 µM). A mutation that rendered both SK2 and SK3 insensitive to apamin and NML produced a current that was still sensitive to DTG. This direct block of SK channels may be important to consider in relation to the pharmacological effects of this compound. [less ▲]

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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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