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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 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 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 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 detailDirect induction of burst firing by SK channel blockade in serotonergic neurons in vivo
Rouchet, Nathalie; Waroux, Olivier ULg; Moreau, Jacqueline ULg et al

Scientific conference (2007, November 04)

Small conductance calcium-activated potassium channels (SK channels) are widely expressed throughout the central nervous system and underlie the medium afterhyperpolarization following a single or a train ... [more ▼]

Small conductance calcium-activated potassium channels (SK channels) are widely expressed throughout the central nervous system and underlie the medium afterhyperpolarization following a single or a train of action potentials. It has been shown that they are involved in the regulation of the excitability and the firing pattern of several types of neurons. In vivo, serotonergic (5-HT) neurons of the dorsal raphe nucleus usually show a tonic pattern of discharge, but they can also display repetitive burst firing activity, usually involving doublets of closely spaced (< 20 ms) action potentials. It has been shown that burst firing is correlated with an increase in transmitter release and postsynaptic effects (Gartside et al., Neuroscience, 98, 295-300, 2000). We hypothesized that SK channels modulate the firing pattern of 5-HT neurons. In a preliminary study, extracellular single-cell recordings combined with iontophoresis showed that UCL1684, a water soluble SK blocker (200 µM), significantly increased the % of spikes produced in bursts in 60% of presumed serotonergic neurons in the anesthetized rat. We confirm here this observation by demonstrating that UCL1684 significantly increased the production of doublets in 17 out of 25 serotonergic neurons. In order to explore whether a GABAergic input was involved in this effect, additional experiments were performed in the presence of the specific GABAA antagonist SR 95531. In these conditions, 50 % (5 out of 10) of serotonergic neurons showed an increase in the production of doublets when UCL 1684 was applied (p = 0.31 vs control), suggesting that a GABAergic input is not implicated in the regulation of the firing pattern of 5-HT neurons by the SK blocker. Finally, the effect of SK channel blockade was explored in vitro in slices. Bath application of the SK blocker apamin (300 nM) did not induce bursting in 15 out of 18 neurons (p < 0.001 vs in vivo control conditions), although it did increase the coefficient of variation of the interspike intervals.Taken together, our results suggest that SK blockade induces burst firing in a majority of dorsal raphe serotonergic neurons. This effect does not involve GABAergic interneurons, but requires an input that is only present in vivo. [less ▲]

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See detailEffect of SK channel blockade on the firing of dorsal raphe neurons in anaesthetized rats
Alleva, Livia ULg; Rouchet, Nathalie; Waroux, Olivier ULg et al

Poster (2006, October 17)

K channels are small conductance calcium-activated potassium channels which trigger an outward current generating an afterhyperpolarization (AHP). This AHP follows a single or a train of action potential ... [more ▼]

K channels are small conductance calcium-activated potassium channels which trigger an outward current generating an afterhyperpolarization (AHP). This AHP follows a single or a train of action potential, and therefore is important in the regulation of the firing frequency and/or pattern of many types of neurons. Serotonergic (5-HT) neurons from the raphe nuclei express SK channels and exhibit a significant AHP which can be efficiently blocked in vitro by apamin and N-methyl laudanosine (NML) (Scuvée-Moreau et al, 2004). In the later study, we found that some but not all neurons (50%) had a significantly increase in their firing rate when positive current was injected after SK channel blockade. In order to determine the physiological relevance of these channels in vivo, single unit extracellular recordings were carried out in anesthetized rats and combined with iontophoresis of the specific non-peptidic SK channel blocker, UCL1684. 5-HT neurons were tested for their inhibitory response to locally applied 5-HT and histological analysis confirmed the localization of the recording site. UCL 1684 was used at a concentration of 200 µM. Out of 11 neurons recorded, 6 showed a significant increase in the production of doublets, with no effect on their mean firing rate as compared to the control condition. The other neurons were completely unaffected. These results suggest that the responsiveness of presumed 5-HT neurons to SK channel block is variable. Although the use of 200 µM UCL allow us to be sure of a sufficient SK blockade at the recording site (Waroux et al, 2005), we can not rule out the possibility that SK channels present at the dendritic level were not completely blocked. In conclusion, SK channels in vivo might play a role in controlling the firing pattern of a subgroup of 5-HT neurons. [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 detailModulation of small conductance calcium-activated potassium (SK) channels: a new challenge in medicinal chemistry.
Liégeois, Jean-François ULg; Mercier, Frédéric ULg; Graulich, Amaury et al

in Current Medicinal Chemistry (2003), 10(8), 625-47

Small conductance calcium-activated potassium (SK) channels are found in many types of neurons as well as in some other cell types. These channels are selective for K(+) and open when intracellular Ca(2 ... [more ▼]

Small conductance calcium-activated potassium (SK) channels are found in many types of neurons as well as in some other cell types. These channels are selective for K(+) and open when intracellular Ca(2+) rises to omega 500 nM. In neurons, this occurs during and after an action potential. Activation of SK channels hyperpolarizes the membrane, thus reducing cell excitability for several tens or hundreds of milliseconds. This phenomenon is called a afterhyperpolarization (AHP). Three subtypes of SK channels (SK1, SK2, SK3) have been cloned and exhibit a differential localization in the brain. SK channels may play a role in physiological and pathological conditions. They may be involved in the control of memory and cognition. Moreover, they are heavily expressed in the basal ganglia (in particular in the substantia nigra, pars compacta) and in the limbic system, suggesting that they may modulate motricity and emotional behaviour. Based on these facts, SK channel subtypes may be a suitable target for developing novel therapeutic agents, but more work is needed to validate these targets. Hence, there is a great need for selective ligands. Moreover, although the risk of peripheral side-effects for SK channel modulators appears to be low, some questions remain to be investigated. Currently, different molecules are known as SK channel modulators. Apamin is a very potent peptidic agent; it produces a strong blockade of these targets which is only very slowly reversible and it has limited selectivity. Dequalinium was found to be an effective blocker. Different chemical modulations on the dequalinium structure led to the discovery of highly potent bis-quinolinium derivatives such as UCL 1684. Other bis-(2-amino-benzimidazole) derivatives are in development. On the other hand, quaternary salts of bicuculline were reported to be effective in inhibiting AHPs. More recent developments on structurally-related molecules revealed that methyl-laudanosine is a new interesting tool for exploring SK channel pharmacology. Finally, a family of compounds has been shown to facilitate SK channel opening. Such compounds may be useful in treating disorders involving neuronal hyperexcitability. [less ▲]

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