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See detailA PREFERENTIAL FOLDED CONFORMATION OF SOME BIS-(8-ISOPROPYL-ISOQUINOLINIUM) DERIVATIVES EXPLAINS STEREOSELECTIVE REDUCTION BY SODIUM BOROHYDRIDE
Dilly, Sébastien ULg; Badarau, Eduard; Dufour, Fabien et al

Poster (2014, June 05)

Small conductance Ca2+-activated K+ (SK) channels play a role in modulating the firing rate and the firing pattern of neurons [Waroux, Eur J Neurosci, 2005, 22, 3111]. A blockade of these targets could be ... [more ▼]

Small conductance Ca2+-activated K+ (SK) channels play a role in modulating the firing rate and the firing pattern of neurons [Waroux, Eur J Neurosci, 2005, 22, 3111]. A blockade of these targets could be useful for the treatment of cognitive dysfunction, neuronal hyperexcitability or dopamine related disorders [Liégeois, Curr Med Chem, 2003, 10, 625]. At the peripheral level, the inhibition of these channels was demonstrated to prevent and terminate atrial fibrillation [Diness, Circ Arrhythm Electrophysiol, 2010, 3, 380]. Moreover, SK channels might represent potential targets for a new class of anticancer agents due to their involvement in breast cancer cell migration [Potier, Mol Cancer Ther, 2006, 5, 2946]. So far, available blockers are not suitable CNS pharmacological tools being either peptides or small molecules with permanent positive charges [Liégeois, Curr Med Chem, 2003, 10, 625; Graulich, J Med Chem, 2007, 50, 5070; Badarau, Bioorg Med Chem Lett, 2011, 21, 6756]. Therefore, symmetrical bis-isoquinolinium compounds have subsequently been transformed to 1,2,3,4-tetrahydroisoquinoline analogues by using sodium borohydride leading to a diastereoisomeric mixture (figure 1) in order to obtain potential CNS-penetrating agents [Graulich, Bioorg Med Chem Lett, 2008, 18, 3440; Neny, Proceedings of the 12th International Conference on In Vivo Methods, Vancouver, Canada, 2008, 267; Koulchitsky, Acta Physiologica, 2009, 195, 670]. Resolution of these mixtures and characterization of the corresponding stereoisomers [Wouters, Eur J Med Chem, 2010, 45, 3240] are necessary before further biological evaluation. In a series of 8- isopropyl analogues, chiral resolution failed for the analogues with propyl and m-xylyl linkers since two and one peaks, respectively, were detected [Nistor, J Pharm Biomed Anal, 2013, 74, 273]. Could these results be explained by an ineffective resolution or would another phenomenon be involved? Further analysis using chiral chromatography, mass spectroscopy and circular dichroism of a sample of the propyl analogue revealed that it is a racemic mixture. X-ray cristallography and conformational analysis indicated a folded conformation of the propyl and m-xylyl analogues (figure 2) responsible for a stereoselective attack of the borohydride reagent during the reduction step. Additional 1H-NMR investigations support structural features detected by theoretical analysis. [less ▲]

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See detailStructural analysis of some bis-(8-isopropyl-isoquinolinium) derivatives reveals a preferential folded conformation leading to a stereoselective attack by sodium borohydride
Dilly, Sébastien ULg; Badarau, Eduard; Dufour, Fabien et al

in Journal of Molecular Structure (2014)

Reduction of symmetrical bis-isoquinolinium derivatives with sodium borohydride generates normally a mixture of three 1,2,3,4-tetrahydroisoquinoline stereoisomers. In a series of 8- isopropyl analogues ... [more ▼]

Reduction of symmetrical bis-isoquinolinium derivatives with sodium borohydride generates normally a mixture of three 1,2,3,4-tetrahydroisoquinoline stereoisomers. In a series of 8- isopropyl analogues, chiral resolution failed for the analogues with propyl and m-xylyl linkers since two and one peaks respectively were detected by HPLC. Further analysis by MS and CD of both peaks of the propyl analogue revealed that each peak corresponds to an enantiomer. Conformational analysis and X-ray cristallography showed a folded conformation of the propyl and m-xylyl analogues responsible for the observed stereoselectivity following the reduction step. Additional 1H NMR investigations confirm structural features detected by theoretical analysis. [less ▲]

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See detailInhibition of PDH Kinase as a new therapeutic target for Age-related Macular Degeneration (AMD)
Arslan, Deniz ULg; Pirotte, Bernard ULg; De Tullio, Pascal ULg et al

Poster (2014, June)

Metabolomics is one of the most recent technologies in the world of Omics sciences. It aims at studying metabolome, which is composed of small molecular weight organic molecules (called metabolites) of a ... [more ▼]

Metabolomics is one of the most recent technologies in the world of Omics sciences. It aims at studying metabolome, which is composed of small molecular weight organic molecules (called metabolites) of a cell, an organism or a biological system. This approach gives rise to a growing number of applications in many areas, such as biomarkers discovery, clinical studies, drug efficacy and toxicity evaluation, diagnostic tools, quality control. One of the most interesting features of metabolomics is its capability to extract biochemical information reflecting biological events and then to be a powerful tool in the knowledge of the aetiology of some pathologies. Indeed, it is clear that every disease could alter more or less drastically the metabolic profile of the patients. Then a metabolomics approach could highlight the biochemical pathways affected and could allow the identification of new putative therapeutic strategies or targets that could be useful in a new drug discovery strategy. As proteomics, metabolomics approach represents a new and powerful tool for Medicinal Chemistry. Age-related Macular Degeneration (AMD) is a leading cause of vision loss in the western world among people aged 50 or older. 90% of all vision loss due to AMD results from the exudative form, which is characterized by choroidal neovascularization (CNV). Age-related changes that induce pathologic CNV are incompletely understood. A successful application of anti-VEGF approaches in the clinic is obviously a turning point in AMD treatment. Nevertheless, despite such important advances, critical issues remain to be addressed. To better understand the aetiology of this pathology, we used and improved a murine model of laser-induced choroidal neovascularization and applied a 1H NMR metabolomics study. This approach leads to the emergence of different putative biomarkers and to the validation of the CNV model for an experimental study of AMD. Among these “biomarkers”, lactate appears to be clearly involved in the development of AMD. The modulation of their plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate DesHydrogenase Kinase inhibitors (PDHK) significantly decrease the impact of laser induced CNV. Starting from these results, the development of new PDHK inhibitors could open the way to innovative treatment opportunities in AMD disease. [less ▲]

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See detailBis-(1,2,3,4-tetrahydroisoquinolinium): a chiral scaffold for developing high affinity ligands for SK channels
Liégeois, Jean-François ULg; Wouters, Johan; Seutin, Vincent ULg et al

in ChemMedChem (2014), 9

N-Methyl-bis-(1,2,3,4-tetrahydroisoquinolinium) analogues derived from AG525 (1,1'-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline)) stereoisomers and tetrandrine, a rigid ... [more ▼]

N-Methyl-bis-(1,2,3,4-tetrahydroisoquinolinium) analogues derived from AG525 (1,1'-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline)) stereoisomers and tetrandrine, a rigid bis-(1,2,3,4-tetrahydroisoquinoline) analogue with an S,S configuration, were synthesized and tested for their affinity for small-conductance calcium-activated potassium channel (SK/KCa2) subtypes using radioligand binding assays. A significant increase in affinity was observed for the quaternized analogues over the parent 1,2,3,4-tetrahydroisoquinoline compounds. Interestingly, the impact of stereochemistry was not the same in the two groups of compounds. For quaternized analogues, affinities of S,S and R,R isomers for SK2 and SK3 channels were similar and in both cases higher than that of the meso derivative. Among the bis-tetrahydroisoquinoline compounds, the S,S isomers exhibited high affinity, while the R,R and meso isomers had similarly lower affinities. Furthermore, the SK2/SK3 selectivity ratio was slightly increased for quaternized analogues. Bis-(1,2,3,4-tetrahydroisoquinolinium) represents a new scaffold for the development of high-affinity ligands for SK channel subtypes [less ▲]

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See detailEnhancing a CH-pi interaction to increase the affinity for 5-HT1A receptors
Liégeois, Jean-François ULg; Lespagnard, Marc; Meneses Salas, Elsa et al

in ACS Medicinal Chemistry Letters (2014), 5

An electrostatic interaction related to a favourable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT1A affinity of a 4-phenyl-1,2,3,6 ... [more ▼]

An electrostatic interaction related to a favourable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared to the corresponding 4-phenylpiperazine analogue. To explore a possible reinforcement of this interaction to increase the affinity for 5-HT1A receptors, different 4-substituted-phenyl analogues were synthesized and tested. The most important increase of affinity is obtained with two electron-donating methyl groups in position 3 and 5 [less ▲]

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See detailIncreased affinity of N-Methyl-AG525 stereoisomers for SK2 and SK3 channels
Liégeois, Jean-François ULg; Seutin, Vincent ULg; Dilly, Sébastien ULg

Poster (2013, November 09)

Small conductance calcium-activated potassium (SK, KCa2) channels represent interesting and challenging targets in medicinal chemistry. So far, the reference ligand is apamin, a peptide used in most ... [more ▼]

Small conductance calcium-activated potassium (SK, KCa2) channels represent interesting and challenging targets in medicinal chemistry. So far, the reference ligand is apamin, a peptide used in most published studies including the [125I] analog for binding studies. Nonpeptidic ligands with high affinity have been developed for several years. Currently, different questions remain to be solved. No selective and brain-penetrating agent is available. In addition, replacing [125I]apamin in binding experiments would be also interesting. We have developed different series of compounds initially derived from laudanosine (1). The quaternized derivative, N-methyl-laudanosine (NML), was found to be a weak SK blocker but highly reversible in electrophysiological experiments (2). Then, bis-charged derivatives were synthesized. Potentially brain-penetrating AG525 stereoisomers were obtained and tested for their affinity for SK channels (3). The affinity of one enantiomer, AG525E1, was found to be close to that of dequalinium (Ki ~ 200 nM) while the two other stereoisomers had a lower affinity. Following this study, quaternization of AG525 stereoisomers was carried out and the affinity of these compounds for SK channel subtypes was determined in comparison with that of parent compounds. We observed a significant increase of affinity for SK2 and SK3 channels for the bis-charged N-methyl derivatives as compared to the basic AG525 stereoisomers to. The ratio of selectivity was increased a little in the case of bis-charged N-methyl derivatives. In addition, the influence of stereochemistry was quite different between both groups. For basic AG525 stereoisomers, the S,S-enantiomer (AG525E1) was the most potent while, within bis-charged N-methyl analogues, both enantiomers had higher affinity. Further in silico approaches should permit to explain these results. References: (1) Graulich et al., Bioorg. Med. Chem. 2005, 13, 1201 (2) Scuvée-Moreau et al., J. Pharmacol. Exp. Ther. 2002, 302, 1176 (3) Graulich et al., Bioorg. Med. Chem. Lett., 2008, 18, 3440 [less ▲]

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See detailCHANGING THE ELECTRONIC DENSITY OF THE DISTAL PHENYL RING OF 4-ARYL-1,2,3,6-TETRAHYDROPYRIDINE DERIVATIVES TO INFLUENCE THE AFFINITY FOR 5-HT1A RECEPTORS
Liégeois, Jean-François ULg; Lespagnard, Marc; Meneses-Salas, Elsa et al

Poster (2013, July)

4-Phenyl-1,2,3,6-tetrahydropyridine(THP) moiety was shown to be favourable compared to the classical 4-phenyl-piperazine in terms of affinity for 5-HT1A receptors in a series of 4-arylpiperazine-ethyl ... [more ▼]

4-Phenyl-1,2,3,6-tetrahydropyridine(THP) moiety was shown to be favourable compared to the classical 4-phenyl-piperazine in terms of affinity for 5-HT1A receptors in a series of 4-arylpiperazine-ethyl carboxamides. The almost planar orientation found in the 4-phenyl-1,2,3,6-THP compounds appeared to be an important spatial requirement for an optimal interaction with the 5-HT1A receptor in this series. This orientation tends to stabilize the ligand binding by an edge-to-face CH-Π interaction between the phenyl ring of the 4-phenyl-1,2,3,6-THP compounds and the side chain of the Phe 6.52 residue in the binding pocket .In the present study, the electronic distribution of the distal benzene ring is modified by introducing substituents with different electronic and/or physicochemical characteristics to explore the impact on this interaction on the affinity for 5-HT1A receptors. These substituents were placed either in 4 or 3 and 5 position of the distal ring in order to avoid a sterical constraint if present in 2 or 6 position. In a quinoxalinamide series, the 3,5-dimethyl substituted analogue has the highest affinity for 5-HT1A receptors as expected. A reinforced interaction with the Phe 6.52 residue might explain this affinity but increased basicity and lipophilicity might also have a role. [less ▲]

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See detailA HYDROGEN BOND INFLUENCES THE 5-HT1A/D4 SELECTIVITY OF WAY-100635 ANALOGUES: AN IN SILICO APPROACH
Dilly, Sébastien ULg; Liégeois, Jean-François ULg

Poster (2013, June)

WAY-100635 is widely used in vitro and in vivo as an antagonist of 5-HT1A receptors. In terms of pharmacological tools and pharmacological investigations, the ideal reference molecule would be highly ... [more ▼]

WAY-100635 is widely used in vitro and in vivo as an antagonist of 5-HT1A receptors. In terms of pharmacological tools and pharmacological investigations, the ideal reference molecule would be highly selective for its target over other related and non-related targets. However WAY-100635 displays affinity for and activity at D4 dopamine receptors, and that "off-target" activity confounds its use in pharmacological studies, particularly when both receptors are present. In this context, we carried out various chemical modifications of the WAY-100635 structure in order to improve its 5-HT1A versus D4 selectivity. An important increase of selectivity was obtained when the basic side chain of WAY-100635 was replaced by a 4-phenylpiperazine or a 4-phenyl-1,2,3,6-tetrahydropyridine moiety. In contrast, the introduction of nitrogen atoms in the acyl group decreased the selectivity by reducing the affinity for 5-HT1A receptors, on the one hand, and enhancing the affinity for D4 receptors on the other hand. In order to explain the reduced 5-HT1A/D4 selectivity of aza-derivatives, the binding modes of the compounds were explored by docking analysis on homology models of the two receptors. It appears that the formation of an additional hydrogen bond within D4 receptors could be the key of the decreased selectivity. These results will be very helpful for developing molecules with an improved 5-HT1A/D4 selectivity. [less ▲]

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See detailThe interactions of apamin and tetraethylammonium are differentially affected by single mutations in the pore mouth of small conductance calcium-activated potassium (SK) channels
Dilly, Sébastien ULg; Philippart, Fabian ULg; Lamy, Cédric et al

in Biochemical Pharmacology (2013), 85

Valine residues in the pore region of SK2 (V366) and SK3 (V520) were replaced by either an alanine or a phenylalanine to evaluate the impact on the interactions with the allosteric blocker apamin. Unlike ... [more ▼]

Valine residues in the pore region of SK2 (V366) and SK3 (V520) were replaced by either an alanine or a phenylalanine to evaluate the impact on the interactions with the allosteric blocker apamin. Unlike TEA which showed high sensitivity to phenylalanine mutated channels, the binding affinity of apamin to the phenylalanine mutants was strongly reduced. In addition, currents from phenylalanine mutants were largely resistant to block by apamin. On the other hand, when the valine residue was replaced by an alanine residue, an increase of the binding affinity and the amount of block by apamin was observed for alanine mutated SK2 channels, but not for mutated SK3 channels. Interestingly, the VA mutation reduced the sensitivity to TEA. In silico data confirmed these experimental results. Therefore, such mutations in the pore region of SK channels show that the three-dimensional structure of the SK tetramers can be disorganized in the outer pore region leading to reduced interaction of apamin with its target. [less ▲]

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See detailPHARMACOMODULATIONS DU WAY-100635 : DE NOUVELLES PISTES DANS LA CONCEPTION D’ANTAGONISTES SÉLECTIFS DES RÉCEPTEURS 5-HT1A
Dilly, Sébastien ULg; Mangin, Floriane; Joly, Benoît ULg et al

Poster (2012, May 24)

Le composé WAY-100635 est un outil pharmacologique abondamment utilisé dans l’exploration des récepteurs sérotoninergiques 5-HT1A. Dès lors, cette molécule de référence devrait présenter une sélectivité ... [more ▼]

Le composé WAY-100635 est un outil pharmacologique abondamment utilisé dans l’exploration des récepteurs sérotoninergiques 5-HT1A. Dès lors, cette molécule de référence devrait présenter une sélectivité importante pour sa cible. Cependant, des travaux récents ont démontré que, à côté de son activité antagoniste des récepteurs 5-HT1A, le WAY-100635 possédait également une affinité et activité conséquentes vis-à-vis des récepteurs dopaminergiques D4, ce qui pourrait limiter son utilisation comme outil pharmacologique. Dans ce contexte, nous avons entrepris diverses modulations structurales de cette molécule de manière à augmenter sa sélectivité vis-à-vis des récepteurs 5-HT1A. Cette sélectivité a été augmentée de manière significative lors du remplacement de la chaîne latérale basique par un groupement 4-phénylpipérazine ou 4-phényl-1,2,3,6-tétrahydropyridine. Une évaluation biologique plus approfondie des deux composés comprenant un profil d’affinité élargi à d’autres récepteurs a confirmé leur sélectivité vis-à-vis des récepteurs 5-HT1A. De plus, des expériences électrophysiologiques sur tranches de cerveau. [less ▲]

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See detailPhysiologie, pharmacologie et modélisation de canaux potassiques : zoom sur les canaux SK
Dilly, Sébastien ULg; Poncin, Sylvie; Lamy, Cédric et al

in Medecine Sciences : M/S (2012), 28

Various types of ion channels are involved in the control of neuronal activity. Among them, SK channels represent an interesting therapeutic target. Indeed, they underlie medium duration ... [more ▼]

Various types of ion channels are involved in the control of neuronal activity. Among them, SK channels represent an interesting therapeutic target. Indeed, they underlie medium duration afterhyperpolarizations in many types of neurons, thus inhibiting cell excitability. A thorough knowledge of the physiology of these channels and the discovery of non-peptidic selective modulators able to pass the blood-brain barrier are essential in view of developing future drugs for brain diseases such as those related to a dysfunction of dopaminergic and serotonergic systems. [less ▲]

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See detailInteractions of apamin with pore mutated SK3 channels
Dilly, Sébastien ULg; Lamy, Cédric; Poncin, Sylvie et al

Poster (2012, March 16)

In the present work, we have tested the impact of the replacement of valine residues in the pore region of SK3 (520) by either an alanine or a phenylalanine residue in terms of the interactions of apamin ... [more ▼]

In the present work, we have tested the impact of the replacement of valine residues in the pore region of SK3 (520) by either an alanine or a phenylalanine residue in terms of the interactions of apamin with these mutants in comparison with the corresponding native channels. Replacing valine residue at position 520 of the SK3 channel by a phenylalanine significantly increased the sensitivity of the channel to be blocked by tetraethylammonium (TEA) as previously reported. Indeed, an aromatic residue, such as a phenylalanine or a tyrosine, is frequently found in the pore region of several potassium channels more sensitive to TEA than SK channels. We measured the affinity (Kd) of apamin in saturation experiments and studied SK currents in transfected cells using patch clamp techniques. In parallel, molecular modelling techniques were used to examine the impact of these local modifications on the interaction of apamin with the corresponding channels. The presence of a phenylalanine in the pore region of potassium channels led to a higher sensitivity for TEA by creating more hydrophobic interactions as found by the docking procedure. In the in vitro binding experiments, the phenylalanine mutant (SK3VF) displayed a very low affinity for apamin. In patch clamp experiments, the SK current was only very partially blocked by apamin in the SK3VF mutant. Furthermore, apamin displayed an affinity and a blocking activity for the alanine mutant close to that for the corresponding native channels. In conclusion, the presence of a bulky and hydrophobic residue at a position near the pore mouth of SK3 channels has a negative impact on their interactions with apamin. [less ▲]

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See detailModerate chemical modifications of WAY-100635 improve the selectivity for 5-HT1A versus D4 receptors
Mangin, Floriane; Dilly, Sébastien ULg; Joly, Benoît ULg et al

in Bioorganic & Medicinal Chemistry Letters (2012)

The selectivity for 5-HT1A versus D4 receptors is significantly increased when the basic side chain of WAY-100635 is replaced by a 4-phenylpiperazine (3e) or a 4-phenyl-1,2,3,6-tetrahydropyridine moiety ... [more ▼]

The selectivity for 5-HT1A versus D4 receptors is significantly increased when the basic side chain of WAY-100635 is replaced by a 4-phenylpiperazine (3e) or a 4-phenyl-1,2,3,6-tetrahydropyridine moiety (3i). The 4-phenyl-1,2,3,6-tetrahydropyridine compounds (3i-l) have a higher affinity for 5-HT1A receptors than do the corresponding unsubstituted phenylpiperazine analogues (3e-h). Compounds 3e and 3i appear to be selective for 5-HT1A receptors over other relevant receptors and still behave as neutral antagonists. [less ▲]

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See detailNew pyridobenzoxazepine derivatives derived from 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13): chemical synthesis and pharmacological evaluation
Liégeois, Jean-François ULg; Deville, Marine; Dilly, Sébastien ULg et al

in Journal of Medicinal Chemistry (2012), 55(1572), 1582

A series of new pyridobenzoxazepine derivatives with various heterocyclic amine side chains were synthesized in order to explore two main parameters related to the distal basic nitrogen. These compounds ... [more ▼]

A series of new pyridobenzoxazepine derivatives with various heterocyclic amine side chains were synthesized in order to explore two main parameters related to the distal basic nitrogen. These compounds were tested for their affinity for dopamine D2L, D4, serotonin 5-HT1A, 5-HT2A and adrenergic 2A receptors in comparison with 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine, JL13 (1) and other diarylazepine derivatives. In terms of multi-receptor target strategy, 2 and 5 present the most promising in vitro binding profile. Bulky, polar and more flexible side chains are not favourable in this context. 2 and 5 were tested in adult rats to evaluate their long-term effects on dopamine and serotonin receptors density in different brain areas. Similar to 1 and other second-generation antipsychotic drugs, repeated treatment with 2 significantly increased D1 and D4 receptors in nucleus accumbens and caudate putamen, and D2 receptors in medial prefrontal cortex and hippocampus while 5 significantly increased D2 and D4 receptors in nucleus accumbens. In addition, 2 increased 5-HT1A and decreased 5-HT2A receptors in cerebral cortex. In contrast, 5 did not alter levels of any 5-HT receptor subtype in any brain region examined. These results encourage further development of 2 as a novel second-generation antipsychotic agent. [less ▲]

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See detailSynthesis and radioligand binding studies of bis-(8-isopropylisoquinolinium) derivatives as ligands for apamin-sensitive sites on cloned SK2 and SK3 channels
Badarau, Eduard; Dilly, Sébastien ULg; Dufour, Fabien et al

in Bioorganic & Medicinal Chemistry Letters (2011), 21(22), 6756-6759

A structure-activity relationship study of N-methyl-laudanosine, a SK channel blocker, has indicated that the 6,7-dimethoxy group could be successfully replaced by a hydrophobic moiety such as an ... [more ▼]

A structure-activity relationship study of N-methyl-laudanosine, a SK channel blocker, has indicated that the 6,7-dimethoxy group could be successfully replaced by a hydrophobic moiety such as an isopropyl substituent in position 8 of the isoquinoline ring. In the present study, bis-(8-isopropyl-isoquinolinium) derivatives (2a-e) were synthesized and tested for their affinity for cloned SK2 and SK3 channels in comparison with their 6,7-dimethoxy analogues (4a-f). Several ligands were investigated, both in flexible (propyl, butyl and pentyl) and rigid (m- or p-xylyl) series, the m-xylyl derivative (2d) having the best profile in terms of affinity and selectivity for SK3/SK2 channels. Molecular studies showed that the optimal conformation of compound 2d fits well with our SK pharmacophore model. [less ▲]

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See detailIon channel modulators: more diversity than previously thought
Dilly, Sébastien ULg; Lamy, Cédric; Marrion, Neil et al

in Chembiochem : A European Journal of Chemical Biology (2011), 12(12), 1808-1812

Ion channel function can be modified in various ways. For example, numerous studies have shown that currents through voltage-gated ion channels are affected by pore block or modification of voltage ... [more ▼]

Ion channel function can be modified in various ways. For example, numerous studies have shown that currents through voltage-gated ion channels are affected by pore block or modification of voltage-dependence of activation/inactivation. Recent experiments performed on various ion channels show that allosteric modulation is an important mechanism to affect channel function. For instance, in KCa2 (formerly SK) channels, the prototypic “blocker” apamin prevents conduction by an allosteric mechanism, while TRPV1 channels are prevented from closing by a tarantula toxin, DkTx, through an interaction with residues located away from the selectivity filter. The recent evidence therefore suggests that, in several ion channels, the region around the outer mouth of the pore is rich in binding sites which may be exploited therapeutically. These discoveries also suggest that the pharmacological vocabulary should be adapted to define these various actions. [less ▲]

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See detailNew substituted aryl esters and aryl amides of 3,4-dihydro-2H-1,2,4- benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors
Dintilhac, Gaëlle ULg; Arslan, Deniz ULg; Dilly, Sébastien ULg et al

in MedChemComm (2011), 2

AMPA receptor potentiators belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been found to be of great interest as cognitive enhancers. Previous structure–activity relationships have ... [more ▼]

AMPA receptor potentiators belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been found to be of great interest as cognitive enhancers. Previous structure–activity relationships have demonstrated the importance for activity of the nature of the substituent at the 7-position of the heterocycle. This work aims to explore the impact on AMPA potentiation of the introduction of different aryl and aralkyl ester or aryl amide groups at the 7-position. The new synthesized compounds were evaluated as AMPA receptor potentiators by examining their effect on rat brain primary cell cultures on AMPA-evoked membrane depolarisation using fluorescent membrane potential dyes and on imaging-based plate reader. The most potent compound of this series was 2-methylphenyl 4-methyl- 3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide 16c which provoked a strong potentiation of AMPA current with a potency close to that reported for the best reference compounds of the benzothiadiazine class (i.e cyclothiazide). This work also revealed that only the ortho-substitution of the phenyl group of 1,2,4-benzothiadiazine-7-carboxylate esters provided potent AMPA receptor potentiators opening the way to further chemical exploration. [less ▲]

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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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