References of "Liégeois, Jean-François"
     in
Bookmark and Share    
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 ▲]

Detailed reference viewed: 3 (1 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 77 (23 ULg)
Full Text
Peer Reviewed
See detailSK channels are on the move
Seutin, Vincent ULg; Liégeois, Jean-François ULg

in British Journal of Pharmacology (2007), 151(5), 568-570

Small-conductance Ca (2+) activated K+ channels (SK channels) underlie the medium duration after hyperpolarization that follows single or trains of action potentials in many types of neurons. Three ... [more ▼]

Small-conductance Ca (2+) activated K+ channels (SK channels) underlie the medium duration after hyperpolarization that follows single or trains of action potentials in many types of neurons. Three subtypes of SK subunits, SK1 (K(Ca)2.1), SK2 (K(Ca)2.2) and SK3 (K(Ca)2.3), have been cloned and are expressed differentially within the central nervous system (CNS). A paper in this issue of BJP reports the discovery of the first example of a positive modulator displaying not only selectivity for SK channels over other channels, but also a subtype selectivity among SK and analogous channels (SK3 > SK2 >> SK1 = IK). Together with other recent progress in the field, this finding enriches the repertoire of tools available to test the hypothesis that SK channels may be targets for future CNS drugs. [less ▲]

Detailed reference viewed: 35 (10 ULg)
Full Text
Peer Reviewed
See detail(+/-)-2-Benzoyl-8-ethyl-1,2-dihydro-isoquinoline-1-carbonitrile: an original Reissert compound
Graulich, Amaury ULg; Norberg, B.; Liégeois, Jean-François ULg et al

in Acta Crystallographica Section E-Structure Reports Online (2007), 63(Part 7), 3161-3073

The title compound, C19H16N2O, is a Reissert compound. The heterocyclic fragment of the molecule exhibits a 1,3-diplanar conformation. The phenyl ring is connected to the isoquinoline ring system via an ... [more ▼]

The title compound, C19H16N2O, is a Reissert compound. The heterocyclic fragment of the molecule exhibits a 1,3-diplanar conformation. The phenyl ring is connected to the isoquinoline ring system via an amide bond that adopts an anti conformation with respect to the adjacent C-N bond in the adjacent heterocyclic ring. Intra-and intermolecular C-H center dot center dot center dot O hydrogen bonds are present in the crystal structure. [less ▲]

Detailed reference viewed: 32 (2 ULg)
Full Text
Peer Reviewed
See detailMetaplastic effect of apamin on LTP and paired-pulse facilitation
Ris, L.; Capron, B.; Sclavons, C. et al

in Learning & Memory (2007), 14(6), 390-399

In area CA1 of hippocampal slices, a single 1-sec train of 100-Hz stimulation generally triggers a short-lasting long-term potentiation (S-LTP) of 1-2 h. Here, we found that when such a train was applied ... [more ▼]

In area CA1 of hippocampal slices, a single 1-sec train of 100-Hz stimulation generally triggers a short-lasting long-term potentiation (S-LTP) of 1-2 h. Here, we found that when such a train was applied 45 min after application of the small conductance Ca2+-activated K+ (SK) channel blocker apamin, it induced a long-lasting LTP (L-LTP) of several hours, instead of an S-LTP. Apamin-induced SK channel blockage is known to resist washing. Nevertheless, the aforementioned effect is not a mere delayed effect; it is metaplastic. Indeed, when a single train was delivered to the Schaffer's collaterals during apamin application, it induced an S-LTP, like in the control situation. At the moment of this LTP induction (15th min of apamin application), the SK channel blockage was nevertheless complete. Indeed, at that time, under the influence of apamin, the amplitude of the series of field excitatory postsynaptic potentials (fEPSPs) triggered by a stimulation train was increased. We found that the metaplastic effect of apamin on LTP was crucially dependent on the NO-synthase pathway, whereas the efficacy of the NMDA receptors was not modified at the time of its occurrence. We also found that apamin produced an increase in paired-pulse facilitation not during, but after, the application of the drug. Finally, we found that the induction of each of these two metaplastic phenomena was mediated by NMDA receptors. A speculative unitary hypothesis to explain these phenomena is proposed. [less ▲]

Detailed reference viewed: 29 (7 ULg)
Full Text
Peer Reviewed
See detailSynthesis and in vitro binding studies of substituted piperidine naphthamides. Part II: Influence of the substitution on the benzyl moiety on the affinity for D-2L, D-4.2, and 5-HT2A receptors
Carato, P.; Graulich, Amaury ULg; Jensen, N. et al

in Bioorganic & Medicinal Chemistry Letters (2007), 17(6), 1570-1574

In continuation of our work on N-(piperidin-4-yl)-naphthamides, the effect of substituted benzyl groups on D-2L, D-4.2, and 5-HT2A receptor affinity was evaluated. In the 1-naphthamide series most ... [more ▼]

In continuation of our work on N-(piperidin-4-yl)-naphthamides, the effect of substituted benzyl groups on D-2L, D-4.2, and 5-HT2A receptor affinity was evaluated. In the 1-naphthamide series most compounds were highly selective for D-4.2 over D-2L, and 5-HT2A receptors. Halogen and methyl substitution in position 3 or 4 of the benzyl group increased D-4.2 affinity. In the 2-naphthamide series a similar high D-4.2 over D-2L selectivity was retained while 5-HT2A affinity was increased. 3-Methoxy, 3-methyl, and 4-methyl substituents were favorable for D-4.2 affinity while halogens reduced affinity. 2-Naphthamides with a 3-bromo- or a 3-methyl group were mixed D-4.2/5-HT2A ligands similar to their unsubstituted parent compound. All compounds from both series with significant affinity for D-4.2 and 5-HT2A receptors were antagonists. (c) 2007 Elsevier Ltd. All rights reserved. [less ▲]

Detailed reference viewed: 20 (3 ULg)
Full Text
Peer Reviewed
See detailSynthesis and in vitro binding studies of substituted piperidine naphthamides. Part I: Influence of the substitution on the basic nitrogen and the position of the amide on the affinity for D-2L, D-4.2, and 5-HT2A receptors
Carato, P.; Graulich, Amaury ULg; Jensen, N. et al

in Bioorganic & Medicinal Chemistry Letters (2007), 17(6), 1565-1569

A series of 1- and 2-naphthamides has been prepared and tested for in vitro binding to D-2L, D-4.2, and 5-HT2A receptors. Different compounds display selectivity for D-4.2 and 5-HT2A receptors versus D-2L ... [more ▼]

A series of 1- and 2-naphthamides has been prepared and tested for in vitro binding to D-2L, D-4.2, and 5-HT2A receptors. Different compounds display selectivity for D-4.2 and 5-HT2A receptors versus D-2L receptors. N-(1-Arylalkyl-piperidin-4-yl) carboxamides have higher affinities than the corresponding N-(4-arylalkylamino-piperidin-1-yl) carboxamide analogues. A benzyl moiety in position 1 of the piperidine in the 2-naphthamide series (2) appears to be the best choice for a favorable interaction with D-4.2 and 5-HT2A receptors. Increasing the linker length between the phenyl ring and the basic nitrogen led to a decreased affinity for these receptors. In the 1-naphthamide series, the most potent D-4.2 ligand (7) possesses a phenylpropyl moiety while its affinity for 5-HT2A receptors is strongly reduced. All compounds with significant affinity for D-4.2 and 5-HT2A receptors were antagonists. (c) 2007 Elsevier Ltd. All rights reserved. [less ▲]

Detailed reference viewed: 138 (0 ULg)
Full Text
Peer Reviewed
See detailLong-term effects of JL 13, a potential atypical antipsychotic, on Ionotropic glutamate receptors
Tarazi, Frank I.; Moran-Gates, Taylor; Gardner, Matthew P. et al

in Journal of Molecular Neuroscience (2007), 32(3), 192-198

Changes in ionotropic glutamate (Glu) N-methyl-D-aspartic acid (NMDA), and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in rat forebrain regions were autoradiographically ... [more ▼]

Changes in ionotropic glutamate (Glu) N-methyl-D-aspartic acid (NMDA), and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in rat forebrain regions were autoradiographically quantified after continuous infusion of JL 13 [(5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine furnarate] for 28 days using osmotic minipumps, and compared to the effects of representative typical (haloperidol) and atypical (clozapine, olanzapine, and risperidone) antipsychotic drugs from previous studies. Similar to other atypical and not typical antipsychotics, JL 13 decreased labeling of NMDA receptors in medial and lateral caudate-putamen (CPu; by 40%). These findings indicate that downregulation of NMDA receptors by JL 13 and other atypical antipsychotic agents in CPu may contribute to their low risk of extrapyramidal side effects. In addition, and similar to olanzapine and risperidone, JL 13 increased AMPA receptor binding in CPu (by 42%). Changes in AMPA receptors may contribute to psychopharmacological properties of JL 13 and other atypical agents. Similar to clozapine, JL 13 did not alter levels of NMDA and AMPA receptors in hippocampus and entorhinal cortex. Long-term effects of JL 13 on ionotropic Glu receptors, as well as on other dopamine and serotonin receptors, support the atypical antipsychotic profile of this novel agent. [less ▲]

Detailed reference viewed: 26 (3 ULg)
Full Text
Peer Reviewed
See detailSynthesis and radioligand binding studies of methoxylated 1,2,3,4-tetrahydroisoquinolinium derivatives as ligands of the apamin-sensitive Ca2+- activated K+ channels
Graulich, Amaury ULg; Scuvée-Moreau, Jacqueline ULg; Alleva, Livia ULg et al

in Journal of Medicinal Chemistry (2006), 49(24), 7208-7214

Several methoxylated 1,2,3,4-tetrahydroisoquinoliniums derived from N-methyl-laudanosine and N-methyl-noscapine were synthesized and evaluated for their affinity for apamin-sensitive binding sites. The ... [more ▼]

Several methoxylated 1,2,3,4-tetrahydroisoquinoliniums derived from N-methyl-laudanosine and N-methyl-noscapine were synthesized and evaluated for their affinity for apamin-sensitive binding sites. The quaternary ammonium derivatives have a higher affinity with regard to the tertiary amines. 6,7-Dimethoxy analogues possess a higher affinity than the 6,8- and 7,8- dimethoxy isomers. A 3,4-dimethoxybenzyl or a 2-naphthylmethyl moiety in C-1 position are more favorable than a 3,4-dimethoxyphenethyl group. Smaller groups such as propyl or isobutyl are unfavorable. In 6,7-dimethoxy analogues, increasing the size and lipophilicity with a naphthyl group in the C-1 position leads to a slight increase of affinity, while the same group in the 6,7,8- trimethoxy series is less favorable. The 6,7,8- trimethoxy derivative 3f is the first tertiary amine in the series to possess an affinity close to that of N-methyl-laudanosine and N-methyl-noscapine. Moreover, electrophysiological studies show that the most effective compound 4f blocks the apamin-sensitive afterhyperpolarization in rat dopaminergic neurons. [less ▲]

Detailed reference viewed: 28 (13 ULg)
Peer Reviewed
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 ▲]

Detailed reference viewed: 16 (1 ULg)
Full Text
Peer Reviewed
See detailLong-term effects of JL 13, a potential atypical antipsychotic, on rat dopamine and serotonin receptor subtypes
Moran-Gates, Taylor; Massari, Carla; Graulich, Amaury ULg et al

in Journal of Neuroscience Research (2006), 84(3), 675-682

Changes in dopamine (DA) D-1, D-2, D-3, and D-4 receptors and serotonin 5-HT1A and 5-HT2A receptors in rat forebrain regions were autoradiographically quantified after continuous infusion of JL 13 [(5-(4 ... [more ▼]

Changes in dopamine (DA) D-1, D-2, D-3, and D-4 receptors and serotonin 5-HT1A and 5-HT2A receptors in rat forebrain regions were autoradiographically quantified after continuous infusion of JL 13 [(5-(4-methylpiperazin-1-yl)8-chloro-pyrido[2,3-b][1,5]benzoxazepine fumarate] for 28 days with osmotic minipumps and compared with the effects of other typical (fluphenazine) and atypical (clozapine, olanzapine, and risperidone) antipsychotic drugs from previous studies. Similar to other typical and atypical antipsychotics, JL 13 increased labeling of D2 receptors in medial prefrontal cortex (MPC) and hippocampus (HIP) and D-4 receptors in nucleus accumbens (NAc), caudate-putamen (CPu), and HIP In addition, JL 13 increased 5-HT1A and decreased 5-HT2A receptors in MPC and dorsolateral frontal cortex (DFC), an effect shared by atypical antipsychotics, and may contribute to their psychopharmacological properties. Clozapine and JL 13, but not other antipsychotics, spared D2 receptors in CPu, which may reflect their ability to induce minimal extrapyramidal side effects. In addition, JL 13 but not other typical and atypical antipsychotic drugs increased abundance of D, receptors in CPu and NAc. JL 13 as well as other antipsychotic agents did not alter levels of forebrain D3 receptors. An atypical-like profile of JL 13 on DA and 5-HT receptor subtypes should encourage further development of this compound as a novel atypical anti psychotic drug. (c) 2006Wiley-Liss, Inc. [less ▲]

Detailed reference viewed: 74 (5 ULg)
Full Text
Peer Reviewed
See detailIdentification of a pharmacophore of SKCa channel blockers
Dilly, Sébastien ULg; Graulich, Amaury ULg; Farce, Amaury et al

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

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

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

Detailed reference viewed: 32 (5 ULg)
Full Text
Peer Reviewed
See detailSK channels control the firing pattern of midbrain dopaminergic neurons in vivo
Waroux, Olivier ULg; Massotte, Laurent ULg; Alleva, Livia ULg et al

in European Journal of Neuroscience (2005), 22(12), 3111-3121

A vast body of experimental in vitro work and modelling studies suggests that the firing pattern and/or rate of a majority of midbrain dopaminergic neurons may be controlled in part by Ca2+-activated K ... [more ▼]

A vast body of experimental in vitro work and modelling studies suggests that the firing pattern and/or rate of a majority of midbrain dopaminergic neurons may be controlled in part by Ca2+-activated K+ channels of the SK type. However, due to the lack of suitable tools, in vivo evidence is lacking. We have taken advantage of the development of the water-soluble, medium potency SK blocker N-methyl-laudanosine (CH3-L) to test this hypothesis in anaesthetized rats. In the lateral ventral tegmental area, CH3-L iontophoresis onto dopaminergic neurons significantly increased the coefficient of variation of their interspike intervals and the percentage of spikes generated in bursts as compared to the control condition. The effect of CH3-L persisted in the presence of a specific GABA(A) antagonist, suggesting a direct effect. It was robust and reversible, and was also observed in the substantia nigra. Control experiments demonstrated that the effect of CH3-L could be entirely ascribed to its blockade of SK channels. On the other hand, the firing pattern of noradrenergic neurons was much less affected by CH3-L. We provide here the first demonstration of a major role of SK channels in the control of the switch between tonic and burst firing of dopaminergic neurons in physiological conditions. This study also suggests a new strategy to develop modulators of the dopaminergic (DA) system, which could be of interest in the treatment of Parkinson's disease, and perhaps other diseases in which DA pathways are dysfunctional. [less ▲]

Detailed reference viewed: 81 (27 ULg)
Full Text
Peer Reviewed
See detailCyproterone and a comparison with its acetate ester
de Ruyck, J.; de Hassonville, S. H.; Liégeois, Jean-François ULg et al

in Acta Crystallographica Section E-Structure Reports Online (2005), 61(Part 11), 3576-3578

The crystal structure of cyproterone (systematic name: 6-chloro-1,2-dihydro-17-hydroxy-30H-cyclopropa[a]pregna-1,4,6- triene-3,20-dione), C22H27ClO3, is compared with cyproterone acetate, a potent anti ... [more ▼]

The crystal structure of cyproterone (systematic name: 6-chloro-1,2-dihydro-17-hydroxy-30H-cyclopropa[a]pregna-1,4,6- triene-3,20-dione), C22H27ClO3, is compared with cyproterone acetate, a potent anti-androgen steroid. The two compounds adopt a similar conformation, except for the cyclopropyl ring attached to the cyclohexenone ring (ring A). Cyproterone further adopts a crystal packing distinct from that of the acetate form. These differences result from hydrogen bonding between the free hydroxy group and the carbonyl group of ring A. [less ▲]

Detailed reference viewed: 20 (0 ULg)
Full Text
Peer Reviewed
See detailSynthesis and radioligand binding studies of C-5- and C-8-substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums as SK channel blockers related to N-methyl-laudanosine and N-methyl-noscapine
Graulich, Amaury ULg; Scuvée-Moreau, Jacqueline ULg; Seutin, Vincent ULg et al

in Journal of Medicinal Chemistry (2005), 48(15), 4972-4982

The synthesis and the 125 I-apamin binding studies of original C-5- and C-8-substituted 143,4-dimethoxy-benzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums and 1-(3,4-dimethoxy-benzyl)-6,6-dimethyl-4,5 ... [more ▼]

The synthesis and the 125 I-apamin binding studies of original C-5- and C-8-substituted 143,4-dimethoxy-benzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums and 1-(3,4-dimethoxy-benzyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridiniums were performed in order to find a reversible and selective SK channel blocker structurally related to N-methyl-laudanosine and N-methyl-noscapine. A bulky alkyl substituent in the C-8 position of the tetrahydroisoquinoline produces a clear increase in the affinity for the apamin sensitive binding sites. The presence of an electron-withdrawing group in the C-5 and C-8 positions is not a suitable substitution for the affinity of drugs structurally related to N-methyl-laudanosine. Thiophenic analogues and 8-methoxy derivatives possess a poor affinity for the apamin sensitive binding sites. Electrophysiological studies performed with the most effective compound showed a blockade of the apamin sensitive afterhyperpolarization in rat dopaminergic neurons. [less ▲]

Detailed reference viewed: 69 (42 ULg)
Full Text
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 ▲]

Detailed reference viewed: 22 (2 ULg)
Full Text
Peer Reviewed
See detailSynthesis and biological evaluation of N-methyl-laudanosine iodide analogues as potential SK channel blockers.
Graulich, A.; Mercier, Frédéric ULg; Scuvée-Moreau, Jacqueline ULg et al

in Bioorganic & Medicinal Chemistry (2005), 13(4), 1201-9

Neuronal action potentials are followed by an afterhyperpolarisation (AHP), which is mediated by small conductance Ca2+-activated K+ channels (SK channels or KCa2 channels). This AHP plays an important ... [more ▼]

Neuronal action potentials are followed by an afterhyperpolarisation (AHP), which is mediated by small conductance Ca2+-activated K+ channels (SK channels or KCa2 channels). This AHP plays an important role in regulating neuronal activity and agents modulating AHP amplitude could have a potential therapeutic interest. It was previously shown that N-methyl-bicuculline iodide blocks SK channels but its GABA) activity represents a serious drawback. In view of the structural analogy between bicuculline and laudanosine 14, several N-quaternary analogues of the latter were developed. It was shown that N-methyl-laudanosine 15 (NML) and N-ethyl-laudanosine 16 induce a reversible and relatively specific blockade of the apamin sensitive AHP in dopaminergic neurones with mean IC50s of 15, and 47 microM, respectively. Laudanosine 14, N-butyl-17 and N-benzyl-18 derivatives were less potent. In order to find pharmacophore elements, modifications were performed at different positions such as C-1, C-6 and C-7. Intracellular recordings on rat midbrain dopaminergic neurones were made in order to evaluate the putative blockade of SK channels by these molecules. Simplified structures such as tetrahydroisoquinoline derivatives with H or Me at C-1 1-6 presented no significant activity at 300 microM. The presence of a 1-(3,4-dimethoxybenzyl) moiety seems an important feature. Indeed, compound 8 showed a blockade of the AHP of only 33% at 300 microM while compound 13 blocked it by 67%, respectively, at the same concentration. Binding experiments were also performed. Binding affinities for SK channels are in good agreement with electrophysiological data. These results indicate that the presence of a charged nitrogen group is an essential point for the affinity on SK channels. Finally, because of the similar activity of both enantiomers of NML 19 and 20, the interaction site may present a symmetrical configuration. [less ▲]

Detailed reference viewed: 97 (55 ULg)
Full Text
Peer Reviewed
See detailElectrophysiological characterization of the SK channel blockers methyl-laudanosine and methyl-noscapine in cell lines and rat brain slices
Scuvée-Moreau, Jacqueline ULg; Boland, André ULg; Graulich, Amaury ULg et al

in British Journal of Pharmacology (2004), 143(6), 753-764

We have recently shown that the alkaloid methyl-laudanosine blocks SK channel-mediated afterhyperpolarizations (AHPs) in midbrain dopaminergic neurones. However, the relative potency of the compound on ... [more ▼]

We have recently shown that the alkaloid methyl-laudanosine blocks SK channel-mediated afterhyperpolarizations (AHPs) in midbrain dopaminergic neurones. However, the relative potency of the compound on the SK channel subtypes and its ability to block AHPs of other neurones were unknown. Using whole-cell patch-clamp experiments in transfected cell lines, we found that the compound blocks SK1, SK2 and SK3 currents with equal potency: its mean IC(50)s were 1.2, 0.8 and 1.8 microM, respectively. IK currents were unaffected. In rat brain slices, methyl-laudanosine blocked apamin-sensitive AHPs in serotonergic neurones of the dorsal raphe and noradrenergic neurones of the locus coeruleus with IC(50)s of 21 and 19 microM, as compared to 15 microM in dopaminergic neurones. However, at 100 microM, methyl-laudanosine elicited a constant hyperpolarization of serotonergic neurones of about 9 mV, which was inconsistently (i.e. not in a reproducible manner) antagonized by atropine and hence partly due to the activation of muscarinic receptors. While exploring the pharmacology of related compounds, we found that methyl-noscapine also blocked SK channels. In cell lines, methyl-noscapine blocked SK1, SK2 and SK3 currents with mean IC(50)s of 5.9, 5.6 and 3.9 microM, respectively. It also did not block IK currents. Methyl-noscapine was slightly less potent than methyl-laudanosine in blocking AHPs in brain slices, its IC(50)s being 42, 37 and 29 microM in dopaminergic, serotonergic and noradrenergic neurones, respectively. Interestingly, no significant non-SK effects were observed with methyl-noscapine in slices. At a concentration of 300 microM, methyl-noscapine elicited the same changes in excitability in the three neuronal types than did a supramaximal concentration of apamin (300 nM). Methyl-laudanosine and methyl-noscapine produced a rapidly reversible blockade of SK channels as compared with apamin. The difference between the IC(50)s of apamin (0.45 nM) and methyl-laudanosine (1.8 microM) in SK3 cells was essentially due to a major difference in their k(-1) (0.028 s(-1) for apamin and >or=20 s(-1) for methyl-laudanosine). These experiments demonstrate that both methyl-laudanosine and methyl-noscapine are medium potency, quickly dissociating, SK channel blockers with a similar potency on the three SK subtypes. Methyl-noscapine may be superior in terms of specificity for the SK channels. [less ▲]

Detailed reference viewed: 103 (31 ULg)
Full Text
Peer Reviewed
See detailDevelopment and validation of a high-performance liquid chromatographic method for the determination of cyproterone acetate in human skin
Henry de Hassonville, Sandrine; Chiap, Patrice ULg; Liégeois, Jean-François ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2004), 36(1), 133-143

In the framework of a preliminary study on the transdermal penetration of cyproterone acetate (CPA), a simple and rapid procedure involving an extraction step coupled to a HPLC-UV determination has been ... [more ▼]

In the framework of a preliminary study on the transdermal penetration of cyproterone acetate (CPA), a simple and rapid procedure involving an extraction step coupled to a HPLC-UV determination has been developed for the separation and quantification of CPA in the two main skin layers-epidermis and dermis-after local application. The separation of epidermis and dermis layers was carefully carried out by means of a sharp spatula after skin immersion in heated water at 65 degrees C. The two skin layers were then treated separately according to the same process: (1) sample homogenization by vibration after freezing with liquid nitrogen in a Mikro-Dismembrator; (2) CPA extraction with methanol after addition of the internal standard (betamethasone dipropionate); (3) centrifugation; (4) evaporation of a supernatant aliquot; (5) dissolution of the dry residue in methanol and addition of water; (6) centrifugation; (7) injection of a supernatant aliquot into the HPLC system. The separation was achieved on octadecylsilica stationary phase using a mobile phase consisting in a mixture of acetonitrile and water (40:60 (v/v)). The method was then validated using a new approach based on accuracy profiles over a CPA concentration range from 33 to 667 ng/ml for each skin layer. Finally, the method was successfully applied to the determination of CPA to several skin samples after topical application of different gel formulations containing CPA. [less ▲]

Detailed reference viewed: 44 (1 ULg)
Full Text
Peer Reviewed
See detailA rapid synthesis of thieno[2,3-c]pyridine and 2-substituted thieno[2,3-c]pyridines
Graulich, Amaury ULg; Liégeois, Jean-François ULg

in Synthesis (2004), (12), 1935-1937

A convenient preparation of thieno[2,3-c]pyridine 3a and of several original 2-substituted-thieno [2,3-c] pyridines 3b-f is achieved by cyclization of the Schiff base resulting from the condensation ... [more ▼]

A convenient preparation of thieno[2,3-c]pyridine 3a and of several original 2-substituted-thieno [2,3-c] pyridines 3b-f is achieved by cyclization of the Schiff base resulting from the condensation between a 2-thiophenecarboxaldehyde 1a-f and aminoacetaldehyde dimethyl acetal. This procedure provides especially good yields in the case of 2-halogenated analogues. [less ▲]

Detailed reference viewed: 42 (3 ULg)