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Jean-françois Liégeois - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and radioligand binding studies of methoxylated 1 2 3 4 tetrahydroisoquinolinium derivatives as ligands of the apamin sensitive ca2 activated k channels
    Journal of Medicinal Chemistry, 2006
    Co-Authors: Amaury Graulich, Vincent Seutin, Jacqueline Scuveemoreau, Livia Alleva, Cedric Lamy, Olivier Waroux, Jean-françois Liégeois
    Abstract:

    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 compo...

  • synthesis 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
    Journal of Medicinal Chemistry, 2005
    Co-Authors: Amaury Graulich, Jacqueline Scuveemoreau, Vincent Seutin, Jean-françois Liégeois
    Abstract:

    The synthesis and the 125I-apamin binding studies of original C-5- and C-8-substituted 1-(3,4-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.

  • synthesis and biological evaluation of n methyl Laudanosine iodide analogues as potential sk channel blockers
    Bioorganic & Medicinal Chemistry, 2005
    Co-Authors: Amaury Graulich, Jacqueline Scuveemoreau, Vincent Seutin, Frederic Mercier, Jean-françois Liégeois
    Abstract:

    Abstract Neuronal action potentials are followed by an afterhyperpolarisation (AHP), which is mediated by small conductance Ca 2+ -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 A 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 IC 50 s of 15, and 47 μM, 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 μM. 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 μM 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.

  • electrophysiological characterization of the sk channel blockers methyl Laudanosine and methyl noscapine in cell lines and rat brain slices
    British Journal of Pharmacology, 2004
    Co-Authors: Jacqueline Scuveemoreau, Andre Boland, Amaury Graulich, Lionel Van Overmeire, Dieter Dhoedt, Fabienne Graulichlorge, Aude Abras, Martin Stocker, Elizabeth Thomas, Jean-françois Liégeois
    Abstract:

    1 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. 2 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 muM, 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 muM, as compared to 15 muM in dopaminergic neurones. However, at 100 muM, 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. 3 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 muM, 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 muM 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 muM, methyl-noscapine elicited the same changes in excitability in the three neuronal types than did a supramaximal concentration of apamin (300 nM). 4 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 muM) in SK3 cells was essentially due to a major difference in their k(-1) (0.028 s(-1) for apamin and greater than or equal to20 s(-1) for methyl-Laudanosine). 5 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.

  • methyl Laudanosine a new pharmacological tool to investigate the function of small conductance ca2 activated k channels
    Journal of Pharmacology and Experimental Therapeutics, 2002
    Co-Authors: Jacqueline Scuveemoreau, Jean-françois Liégeois, Laurent Massotte, Vincent Seutin
    Abstract:

    Small-conductance Ca2+-activated K+ channels (SK channels) underlie the prolonged postspike afterhyperpolarization (AHP) observed in many central neurons and play an important role in modulating neuronal activity. However, a lack of specific and reversible blockers of these channels hampers their study in various experimental conditions. Because previous work has shown that bicuculline salts block these channels, we examined whether related alkaloids, namely Laudanosine quaternary derivatives, would produce similar effects. Intracellular recordings were performed on rat midbrain dopaminergic neurons and hippocampus CA1 pyramidal cells. Binding experiments were performed on rat cerebral cortex membranes. Laudanosine, methyl-Laudanosine, and ethyl-Laudanosine blocked the apamin-sensitive AHP of dopaminergic neurons with mean IC50 values of 152, 15, and 47 μM, respectively. The benzyl and butyl derivatives were less potent. Methyl-Laudanosine had no effect on the Ih current, action potential parameters, or membrane resistance of dopaminergic cells, or on the decrease in input resistance induced by muscimol, indicating a lack of antagonism at GABAA receptors. Interestingly, 100 μM methyl-Laudanosine induced a significant increase in spiking frequency of dopaminergic neurons but not of CA1 pyramidal cells, suggesting the possibility of regional selectivity. Binding experiments on Laudanosine derivatives were in good agreement with electrophysiological data. Moreover, methyl-Laudanosine has no affinity for voltage-gated potassium channels, and its affinity for SK channels (IC504 μM) is superior to its affinity for muscarinic (IC50114 μM) and neuronal nicotinic (IC50 ≥367 μM) receptors . Methyl-Laudanosine may be a valuable pharmacological tool to investigate the role of SK channels in various experimental models.

Amaury Graulich - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and radioligand binding studies of methoxylated 1 2 3 4 tetrahydroisoquinolinium derivatives as ligands of the apamin sensitive ca2 activated k channels
    Journal of Medicinal Chemistry, 2006
    Co-Authors: Amaury Graulich, Vincent Seutin, Jacqueline Scuveemoreau, Livia Alleva, Cedric Lamy, Olivier Waroux, Jean-françois Liégeois
    Abstract:

    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 compo...

  • synthesis 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
    Journal of Medicinal Chemistry, 2005
    Co-Authors: Amaury Graulich, Jacqueline Scuveemoreau, Vincent Seutin, Jean-françois Liégeois
    Abstract:

    The synthesis and the 125I-apamin binding studies of original C-5- and C-8-substituted 1-(3,4-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.

  • synthesis and biological evaluation of n methyl Laudanosine iodide analogues as potential sk channel blockers
    Bioorganic & Medicinal Chemistry, 2005
    Co-Authors: Amaury Graulich, Jacqueline Scuveemoreau, Vincent Seutin, Frederic Mercier, Jean-françois Liégeois
    Abstract:

    Abstract Neuronal action potentials are followed by an afterhyperpolarisation (AHP), which is mediated by small conductance Ca 2+ -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 A 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 IC 50 s of 15, and 47 μM, 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 μM. 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 μM 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.

  • electrophysiological characterization of the sk channel blockers methyl Laudanosine and methyl noscapine in cell lines and rat brain slices
    British Journal of Pharmacology, 2004
    Co-Authors: Jacqueline Scuveemoreau, Andre Boland, Amaury Graulich, Lionel Van Overmeire, Dieter Dhoedt, Fabienne Graulichlorge, Aude Abras, Martin Stocker, Elizabeth Thomas, Jean-françois Liégeois
    Abstract:

    1 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. 2 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 muM, 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 muM, as compared to 15 muM in dopaminergic neurones. However, at 100 muM, 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. 3 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 muM, 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 muM 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 muM, methyl-noscapine elicited the same changes in excitability in the three neuronal types than did a supramaximal concentration of apamin (300 nM). 4 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 muM) in SK3 cells was essentially due to a major difference in their k(-1) (0.028 s(-1) for apamin and greater than or equal to20 s(-1) for methyl-Laudanosine). 5 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.

Jacqueline Scuveemoreau - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and radioligand binding studies of methoxylated 1 2 3 4 tetrahydroisoquinolinium derivatives as ligands of the apamin sensitive ca2 activated k channels
    Journal of Medicinal Chemistry, 2006
    Co-Authors: Amaury Graulich, Vincent Seutin, Jacqueline Scuveemoreau, Livia Alleva, Cedric Lamy, Olivier Waroux, Jean-françois Liégeois
    Abstract:

    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 compo...

  • synthesis 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
    Journal of Medicinal Chemistry, 2005
    Co-Authors: Amaury Graulich, Jacqueline Scuveemoreau, Vincent Seutin, Jean-françois Liégeois
    Abstract:

    The synthesis and the 125I-apamin binding studies of original C-5- and C-8-substituted 1-(3,4-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.

  • synthesis and biological evaluation of n methyl Laudanosine iodide analogues as potential sk channel blockers
    Bioorganic & Medicinal Chemistry, 2005
    Co-Authors: Amaury Graulich, Jacqueline Scuveemoreau, Vincent Seutin, Frederic Mercier, Jean-françois Liégeois
    Abstract:

    Abstract Neuronal action potentials are followed by an afterhyperpolarisation (AHP), which is mediated by small conductance Ca 2+ -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 A 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 IC 50 s of 15, and 47 μM, 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 μM. 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 μM 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.

  • electrophysiological characterization of the sk channel blockers methyl Laudanosine and methyl noscapine in cell lines and rat brain slices
    British Journal of Pharmacology, 2004
    Co-Authors: Jacqueline Scuveemoreau, Andre Boland, Amaury Graulich, Lionel Van Overmeire, Dieter Dhoedt, Fabienne Graulichlorge, Aude Abras, Martin Stocker, Elizabeth Thomas, Jean-françois Liégeois
    Abstract:

    1 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. 2 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 muM, 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 muM, as compared to 15 muM in dopaminergic neurones. However, at 100 muM, 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. 3 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 muM, 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 muM 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 muM, methyl-noscapine elicited the same changes in excitability in the three neuronal types than did a supramaximal concentration of apamin (300 nM). 4 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 muM) in SK3 cells was essentially due to a major difference in their k(-1) (0.028 s(-1) for apamin and greater than or equal to20 s(-1) for methyl-Laudanosine). 5 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.

  • methyl Laudanosine a new pharmacological tool to investigate the function of small conductance ca2 activated k channels
    Journal of Pharmacology and Experimental Therapeutics, 2002
    Co-Authors: Jacqueline Scuveemoreau, Jean-françois Liégeois, Laurent Massotte, Vincent Seutin
    Abstract:

    Small-conductance Ca2+-activated K+ channels (SK channels) underlie the prolonged postspike afterhyperpolarization (AHP) observed in many central neurons and play an important role in modulating neuronal activity. However, a lack of specific and reversible blockers of these channels hampers their study in various experimental conditions. Because previous work has shown that bicuculline salts block these channels, we examined whether related alkaloids, namely Laudanosine quaternary derivatives, would produce similar effects. Intracellular recordings were performed on rat midbrain dopaminergic neurons and hippocampus CA1 pyramidal cells. Binding experiments were performed on rat cerebral cortex membranes. Laudanosine, methyl-Laudanosine, and ethyl-Laudanosine blocked the apamin-sensitive AHP of dopaminergic neurons with mean IC50 values of 152, 15, and 47 μM, respectively. The benzyl and butyl derivatives were less potent. Methyl-Laudanosine had no effect on the Ih current, action potential parameters, or membrane resistance of dopaminergic cells, or on the decrease in input resistance induced by muscimol, indicating a lack of antagonism at GABAA receptors. Interestingly, 100 μM methyl-Laudanosine induced a significant increase in spiking frequency of dopaminergic neurons but not of CA1 pyramidal cells, suggesting the possibility of regional selectivity. Binding experiments on Laudanosine derivatives were in good agreement with electrophysiological data. Moreover, methyl-Laudanosine has no affinity for voltage-gated potassium channels, and its affinity for SK channels (IC504 μM) is superior to its affinity for muscarinic (IC50114 μM) and neuronal nicotinic (IC50 ≥367 μM) receptors . Methyl-Laudanosine may be a valuable pharmacological tool to investigate the role of SK channels in various experimental models.

Vincent Seutin - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and radioligand binding studies of methoxylated 1 2 3 4 tetrahydroisoquinolinium derivatives as ligands of the apamin sensitive ca2 activated k channels
    Journal of Medicinal Chemistry, 2006
    Co-Authors: Amaury Graulich, Vincent Seutin, Jacqueline Scuveemoreau, Livia Alleva, Cedric Lamy, Olivier Waroux, Jean-françois Liégeois
    Abstract:

    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 compo...

  • synthesis 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
    Journal of Medicinal Chemistry, 2005
    Co-Authors: Amaury Graulich, Jacqueline Scuveemoreau, Vincent Seutin, Jean-françois Liégeois
    Abstract:

    The synthesis and the 125I-apamin binding studies of original C-5- and C-8-substituted 1-(3,4-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.

  • synthesis and biological evaluation of n methyl Laudanosine iodide analogues as potential sk channel blockers
    Bioorganic & Medicinal Chemistry, 2005
    Co-Authors: Amaury Graulich, Jacqueline Scuveemoreau, Vincent Seutin, Frederic Mercier, Jean-françois Liégeois
    Abstract:

    Abstract Neuronal action potentials are followed by an afterhyperpolarisation (AHP), which is mediated by small conductance Ca 2+ -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 A 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 IC 50 s of 15, and 47 μM, 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 μM. 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 μM 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.

  • methyl Laudanosine a new pharmacological tool to investigate the function of small conductance ca2 activated k channels
    Journal of Pharmacology and Experimental Therapeutics, 2002
    Co-Authors: Jacqueline Scuveemoreau, Jean-françois Liégeois, Laurent Massotte, Vincent Seutin
    Abstract:

    Small-conductance Ca2+-activated K+ channels (SK channels) underlie the prolonged postspike afterhyperpolarization (AHP) observed in many central neurons and play an important role in modulating neuronal activity. However, a lack of specific and reversible blockers of these channels hampers their study in various experimental conditions. Because previous work has shown that bicuculline salts block these channels, we examined whether related alkaloids, namely Laudanosine quaternary derivatives, would produce similar effects. Intracellular recordings were performed on rat midbrain dopaminergic neurons and hippocampus CA1 pyramidal cells. Binding experiments were performed on rat cerebral cortex membranes. Laudanosine, methyl-Laudanosine, and ethyl-Laudanosine blocked the apamin-sensitive AHP of dopaminergic neurons with mean IC50 values of 152, 15, and 47 μM, respectively. The benzyl and butyl derivatives were less potent. Methyl-Laudanosine had no effect on the Ih current, action potential parameters, or membrane resistance of dopaminergic cells, or on the decrease in input resistance induced by muscimol, indicating a lack of antagonism at GABAA receptors. Interestingly, 100 μM methyl-Laudanosine induced a significant increase in spiking frequency of dopaminergic neurons but not of CA1 pyramidal cells, suggesting the possibility of regional selectivity. Binding experiments on Laudanosine derivatives were in good agreement with electrophysiological data. Moreover, methyl-Laudanosine has no affinity for voltage-gated potassium channels, and its affinity for SK channels (IC504 μM) is superior to its affinity for muscarinic (IC50114 μM) and neuronal nicotinic (IC50 ≥367 μM) receptors . Methyl-Laudanosine may be a valuable pharmacological tool to investigate the role of SK channels in various experimental models.

  • Methyl-Laudanosine: A new pharmacological tool to investigate the function of small-conductance Ca2+-activated K+ channels
    2002
    Co-Authors: Jacqueline Scuvee-moreau, Jean-françois Liégeois, Laurent Massotte, Vincent Seutin
    Abstract:

    ABSTRACT Small-conductance Ca 2ϩ -activated K ϩ channels (SK channels) underlie the prolonged postspike afterhyperpolarization (AHP) observed in many central neurons and play an important role in modulating neuronal activity. However, a lack of specific and reversible blockers of these channels hampers their study in various experimental conditions. Because previous work has shown that bicuculline salts block these channels, we examined whether related alkaloids, namely Laudanosine quaternary derivatives, would produce similar effects. Intracellular recordings were performed on rat midbrain dopaminergic neurons and hippocampus CA1 pyramidal cells. Binding experiments were performed on rat cerebral cortex membranes. Laudanosine, methyl-Laudanosine, and ethyl-Laudanosine blocked the apamin-sensitive AHP of dopaminergic neurons with mean IC 50 values of 152, 15, and 47 M, respectively. The benzyl and butyl derivatives were less potent. Methyl-Laudanosine had no effect on the I h current, action potential parameters, or membrane resistance of dopaminergic cells, or on the decrease in input resistance induced by muscimol, indicating a lack of antagonism at GABA A receptors. Interestingly, 100 M methylLaudanosine induced a significant increase in spiking frequency of dopaminergic neurons but not of CA1 pyramidal cells, suggesting the possibility of regional selectivity. Binding experiments on Laudanosine derivatives were in good agreement with electrophysiological data. Moreover, methyl-Laudanosine has no affinity for voltage-gated potassium channels, and its affinity for SK channels (IC 50 4 M) is superior to its affinity for muscarinic (IC 50 114 M) and neuronal nicotinic (IC 50 Ն367 M) receptors . Methyl-Laudanosine may be a valuable pharmacological tool to investigate the role of SK channels in various experimental models. Other than neurotransmitter receptors and transporters, ion channels constitute an attractive target to develop new drugs that will be active on the central nervous system. Currently, the only ion channel that is well established as a central nervous system target is the voltage-gated Na ϩ channel, which is blocked by antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine Evidence suggests that SK-channel modulation may be interesting in a range of central nervous system disorders, This work was supported in part by Grant 3.4525.98 from the National Fund for Scientific Research (Brussels, Belgium). This work has been presented in meeting abstract form: Scuvée-Moreau J, Liégeois JF, and Seutin V (2002) Effect of Laudanosine derivatives on the apamin-sensitive afterhyperpolarization of rat dopaminergic neurons-identification of methyl-Laudanosine as a new specific blocker (Abstract). Fundam Clin Pharmacol 16:67

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  • Total Synthesis of (-)-Oxycodone via Anodic Aryl-Aryl Coupling.
    Organic letters, 2019
    Co-Authors: Alexander Lipp, Siegfried R. Waldvogel, Maximilian Selt, Dorota Ferenc, Dieter Schollmeyer, Till Opatz
    Abstract:

    A fully regio- and diastereoselective electrochemical 4a–2′-coupling of a 3′,4′,5′-trioxygenated Laudanosine derivative enables the synthesis of the corresponding morphinandienone. This key intermediate is further transformed into (−)-oxycodone through conjugate nucleophilic substitution for E-ring closure and [4 + 2] cycloaddition with photogenerated singlet oxygen to accomplish diastereoselective hydroxylation at C-14. The anodic transformation provides high yields and can be performed under constant current conditions both in a simple undivided cell or in continuous flow.

  • Total Synthesis of (−)-Oxycodone via Anodic Aryl–Aryl Coupling
    2019
    Co-Authors: Alexander Lipp, Siegfried R. Waldvogel, Maximilian Selt, Dorota Ferenc, Dieter Schollmeyer, Till Opatz
    Abstract:

    A fully regio- and diastereoselective electrochemical 4a–2′-coupling of a 3′,4′,5′-trioxygenated Laudanosine derivative enables the synthesis of the corresponding morphinandienone. This key intermediate is further transformed into (−)-oxycodone through conjugate nucleophilic substitution for E-ring closure and [4 + 2] cycloaddition with photogenerated singlet oxygen to accomplish diastereoselective hydroxylation at C-14. The anodic transformation provides high yields and can be performed under constant current conditions both in a simple undivided cell or in continuous flow

  • synthesis of alkaloids by stevens rearrangement of nitrile stabilized ammonium ylides Laudanosine laudanidine armepavine 7 methoxycryptopleurine and xylopinine
    Journal of Organic Chemistry, 2013
    Co-Authors: Julio Cesar Orejarena Pacheco, Günther Lahm, Till Opatz
    Abstract:

    The Stevens rearrangement of nitrile-stabilized ammonium ylides in conjunction with the reductive removal of the nitrile function permits the facile construction of α-branched amines from α-aminonitriles. We employed this reaction sequence for the preparation of (±)-Laudanosine, (±)-laudanidine and (±)-armepavine, (±)-7-methoxycryptopleurine, and (±)-xylopinine from two closely related and readily accessible bicyclic α-aminonitriles. The final products were obtained in high to almost quantitative yields (71–98%) from the quaternary ammonium salts obtained by N-alkylation of these starting materials.

  • Synthesis of Alkaloids by Stevens Rearrangement of Nitrile-Stabilized Ammonium Ylides: (±)-Laudanosine, (±)-Laudanidine, (±)-Armepavine, (±)-7-Methoxycryptopleurine, and (±)-Xylopinine
    2013
    Co-Authors: Julio Cesar Orejarena Pacheco, Günther Lahm, Till Opatz
    Abstract:

    The Stevens rearrangement of nitrile-stabilized ammonium ylides in conjunction with the reductive removal of the nitrile function permits the facile construction of α-branched amines from α-aminonitriles. We employed this reaction sequence for the preparation of (±)-Laudanosine, (±)-laudanidine and (±)-armepavine, (±)-7-methoxycryptopleurine, and (±)-xylopinine from two closely related and readily accessible bicyclic α-aminonitriles. The final products were obtained in high to almost quantitative yields (71–98%) from the quaternary ammonium salts obtained by N-alkylation of these starting materials