M-type channels selectively control bursting in rat dopaminergic neurons

in European Journal of Neuroscience (2010), 31

Combined experimental and computational approaches to study the action of blockers of small conductance calcium-activated potassium (SK) channels

in Acta Physiologica Scandinavica (2010), 199(supplement 678), -10

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system (CNS) and underlie medium duration afterhyperpolarizations in many types of neurons ... [more ▼]

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system (CNS) and underlie medium duration afterhyperpolarizations in many types of neurons. Three subtypes of SK channels, SK1, SK2 and SK3, have been identified so far in different parts of the brain. Blocking SK channels might be beneficial in the treatment of several CNS disorders such as depression, Parkinson’s disease and cognitive disorders. Until now, the precise site of interaction between these channels and their blockers has not yet been elucidated. In this context, molecular modeling is a theoretical approach that can quickly provide ideas on the binding mode of SK blockers. We first performed homology modeling of the S5-H5-S6 portion of the channels on the basis of the crystal structure of the KcsA potassium channel (Zhou et al. Nature. 2001, 414, 43-48). The binding sites of N-methyl-laudanosine (NML) (Scuvée-Moreau et al. J. Pharmacol. Exp. Ther. 2002, 302, 1176-83), a non-selective and non-peptidic ligand, and apamin (Blatz et al. Nature. 1986, 323, 718-20), an octadecapeptide with a preference for the SK2 subtype, were subsequently explored by docking analysis. Different amino-acids were suggested to interact with the two blockers. The docking of NML revealed a binding site in the turret region, far from the pore. The docking of apamin identified a very large binding site that includes a portion of the site of NML. In order to confirm the predicted binding sites, site-directed mutagenesis was used. The first mutant channels tested in electrophysiological experiments by the patch clamp technique validated some of the theoretical data. Using this strategy, we hope to get a better understanding of the mechanism of action of SK blockers and eventually find strategies to obtain subtype-selective blockers. [less ▲]

Conformational analysis of new 5-HT1A ligands by molecular modeling

Conference (2009, May 14)

5-HT1A receptors represent a major target for research and drug development due to their involvement in pathologies such as anxiety,1 depression,2 sleep and memory disorders,3,4 and schizophrenia.5 The ... [more ▼]

5-HT1A receptors represent a major target for research and drug development due to their involvement in pathologies such as anxiety,1 depression,2 sleep and memory disorders,3,4 and schizophrenia.5 The main feature of many drugs having a 5-HT1A affinity is the presence of arylpiperazine moiety.6 Indeed, the protonated nitrogen and the aromatic ring of the arylpiperazine compounds are considered crucial for the interaction with the receptor.7 Interestingly, an in vitro binding study realized in our laboratory reveals the presence of the 1,2,3,6-tetrahydropyridine instead of the piperazine moiety in 4-arylpiperazine-ethyl carboxamide derivatives is highly favourable for 5-HT1A affinity. In order to better understand the favourable effect of this chemical modification, we have performed a conformational analysis of these compounds mainly based on the position of the phenyl ring relative to the piperazine and tetrahydropyridine ones. In the piperazine compounds, the phenyl ring is found in a perpendicular orientation, whereas an almost planar orientation seems to be the most favourable conformation for the tetrahydropyridine compounds (See figure). Therefore, the almost planar orientation of the 4-substituted phenyl ring appears as an important spatial requirement for an optimal interaction with the receptor binding site. This finding could lead to new ideas in the design of high-affinity 5-HT1A ligands. [less ▲]

SK Channel blockade promotes burst firing in dorsal raphe serotonergic neurons

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

SK Channel blockade promotes bursting in vivo in dorsal raphe serotonergic neurons

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

Bis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca2+-activated K+ channel blockers

in Bioorganic & Medicinal Chemistry Letters (2008), 18(11), 3440-3445

So far, small conductance Ca2+-activated K+ channel (SK) blockers mostly consist of quaternary ammonium derivatives or peptides. Due to their physicochemical properties, these blockers are not suitable to ... [more ▼]

So far, small conductance Ca2+-activated K+ channel (SK) blockers mostly consist of quaternary ammonium derivatives or peptides. Due to their physicochemical properties, these blockers are not suitable to study the physiological roles of SK channels in the central nervous system in vivo. Herein, we report the discovery of a chiral bis-tertiary amine with SK blocking properties from chemical modulation of laudanosine. AG525E1 has an affinity for SK channels (K-i = 293 nM) approximately 100-fold higher than the tertiary compound laudanosine (K-i similar to 30 mu M) and similar to the charged compound dequalinium (K-i = 221 nM). AG525E1 equipotently blocks SK1, SK2 and SK3 currents in transfected cell lines. Because of its basic and lipophilic properties, it can reach central SK targets. (c) 2008 Elsevier Ltd. All rights reserved. [less ▲]

SK channels are on the move

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 ▲]

Metaplastic effect of apamin on LTP and paired-pulse facilitation

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 ▲]

Synthesis 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

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 ▲]

Synthesis and radioligand binding studies of methoxylated 1,2,3,4-tetrahydroisoquinolinium derivatives as ligands of the apamin-sensitive Ca2+- activated K+ channels

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 ▲]