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Modulation of small conductance calcium-activated potassium (SK) channels: a new challenge in medicinal chemistry.
TLDR
Small conductance calcium-activated potassium (SK) channels are found in many types of neurons as well as in some other cell types, and are heavily expressed in the basal ganglia and in the limbic system, suggesting that they may modulate motricity and emotional behaviour. Expand
SK channels control the firing pattern of midbrain dopaminergic neurons in vivo
TLDR
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 is provided, which suggests a new strategy to develop modulators of the dopamine (DA) system. Expand
Electrophysiological characterization of the SK channel blockers methyl‐laudanosine and methyl‐noscapine in cell lines and rat brain slices
TLDR
Both methyl‐laudanosine and methyl‐noscapine are medium potency, quickly dissociating, SK channel blockers with a similar potency on the three SK subtypes and may be superior in terms of specificity for the SK channels. Expand
Synthesis and radioligand binding studies of methoxylated 1,2,3,4-tetrahydroisoquinolinium derivatives as ligands of the apamin-sensitive Ca2+-activated K+ channels.
TLDR
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, and electrophysiological studies show that the most effective compound 4f blocks the apamin-sensitive afterhyperpolarization in rat dopaminergic neurons. Expand
Synthesis and radioligand binding studies of bis-isoquinolinium derivatives as small conductance Ca(2+)-activated K(+) channel blockers.
TLDR
The original bis-isoquinolinium derivatives were synthezised and evaluated using binding studies, electrophysiology, and molecular modeling and demonstrate the blocking potential of the apamin-sensitive after-hyperpolarization. Expand
Synthesis and biological evaluation of N-methyl-laudanosine iodide analogues as potential SK channel blockers.
TLDR
Results indicate that the presence of a charged nitrogen group is an essential point for the affinity on SK channels and that because of the similar activity of both enantiomers of NML 19 and 20, the interaction site may present a symmetrical configuration. Expand
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
TLDR
Electrophysiological studies showed a blockade of the apamin sensitive afterhyperpolarization in rat dopaminergic neurons, and a bulky alkyl substituent in the C-8 position of the tetrahydroisoquinoline produces a clear increase in the affinity for the apamination sensitive binding sites. Expand
Identification of a pharmacophore of SKCa channel blockers
TLDR
In this study, a pharmacophoric model of SK channels blockers is presented, based on a series of nonpeptidic compounds and apamin, a peptidic blocker, to create the pharmacophore model. Expand
Chemical Modifications on 4-Arylpiperazine-Ethyl Carboxamide Derivatives Differentially Modulate Affinity for 5-HT1A, D4.2, and α2A Receptors: Synthesis and In Vitro Radioligand Binding Studies
A series of substituted 4-aryl-piperazine-ethyl heteroarylcarboxamides were prepared and tested in in vitro radioligand binding studies. The presence of a quinoxaline has a favourable impact in termsExpand
Bis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca(2+)-activated K(+) channel blockers.
TLDR
AG525E1 is the discovery of a chiral bis-tertiary amine with SK blocking properties from chemical modulation of laudanosine, which has an affinity for SK channels and can reach central SK targets. Expand
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