References of "Liégeois, Jean-François"
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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 detailChemical Modifications on 4-Arylpiperazine-Ethyl Carboxamide Derivatives Differentially Modulate Affinity for 5-HT1A, D4.2, and alpha(2A) Receptors: Synthesis and In Vitro Radioligand Binding Studies
Graulich, Amaury; Léonard, Marc ULg; Résimont, Mélissa et al

in Australian Journal of Chemistry (2010), 63

A series of substituted 4-aryl-piperazine ethyl heteroarylcarboxamides were prepared and tested in in vitro radioligand binding studies. The presence of a quinoxaline has a favourable impact in terms of ... [more ▼]

A series of substituted 4-aryl-piperazine ethyl heteroarylcarboxamides were prepared and tested in in vitro radioligand binding studies. The presence of a quinoxaline has a favourable impact in terms of serotonin 5-HT1A versus dopamine D4.2 receptor selectivity. Compounds with a 3-CF3 group at the distal phenyl ring are the most effective in terms of affinity and selectivity for 5-HT1A versus D4.2 receptors. A 4-phenyl-1,2,3,6-tetrahydropyridine in replacement of the corresponding 4-phenyl-piperazine side chain is also favourable not only for the affinity for 5-HT1A and D4.2 receptors but also in some cases for 2A-adrenoceptors. [less ▲]

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See detailAllosteric block of KCa2 channels by apamin
Lamy, Cédric ULg; Goodchild, Samuel J; Weatherall, Kate L et al

in Journal of Biological Chemistry (2010)

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See detailM-type channels selectively control bursting in rat dopaminergic neurons
Drion, Guillaume ULg; Bonjean, Maxime; Waroux, Olivier ULg et al

in European Journal of Neuroscience (2010), 31

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See detailBis-tetrahydroisoquinoline derivatives: Structure analysis of the three stereoisomers of 1,1'-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline)
Wouters, Johan; Elasaad, Kossay; Norberg, Bernadette et al

in European Journal of Medicinal Chemistry (2010), 45

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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 detailSK Channel blockade promotes burst firing in dorsal raphe serotonergic neurons
Rouchet, Nathalie; Waroux, Olivier ULg; Lamy, Cédric et al

in European Journal of Neuroscience (2008), 28(6), 1108-15

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See detailSK Channel blockade promotes burst firing in dorsal raphe serotonergic neurons
Rouchet, Nathalie ULg; Waroux, Olivier ULg; Lamy, Cédric ULg et al

in European Journal of Neuroscience (2008), 28(6), 1108-15

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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 detailSK Channel blockade promotes bursting in vivo in dorsal raphe serotonergic neurons
Rouchet, Nathalie; Waroux, Olivier ULg; Alix, Philippe ULg et al

in Acta Physiologica (2008, May 17), 194(supll. 666), -01

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See detailThe SK channel blocker AG525E1 increases locomotor activity and in vivo dopamine release in the rat nucleus accumbens
Neny, M.; Lemmer, Y.; Graulich, A. et al

in Phillips, P. E. M.; Sandberg, S. G.; Ahn, S. (Eds.) et al Monitoring Molecules in Neuroscience - Proceedings of the 12th International Conference on In Vivo Methods (2008)

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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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