| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg | |||
| Other Sizes |
| Targets |
The primary target of NS8593 HCl is the small conductance calcium-activated potassium (SK/KCa2) channel family, comprising SK1, SK2, and SK3 subtypes. It acts as a potent negative gating modulator of these channels, decreasing their calcium sensitivity and reducing their activity. NS8593 HCl reversibly inhibits SK3-mediated currents with a Kd of 77 nM. It inhibits all SK1-3 subtypes in a calcium-dependent manner, with Kd values of 0.42 μM for SK1, 0.60 μM for SK2, and 0.73 μM for SK3 in the presence of 0.5 μM calcium. The compound does not affect intermediate-conductance (IK) or large-conductance (BK) calcium-activated potassium channels. By inhibiting SK channels, NS8593 HCl reduces the afterhyperpolarization that follows action potentials, thereby increasing neuronal excitability.
|
|---|---|
| ln Vitro |
The inhibitory impact of NS8593 (Compound 14) in excised patches was observed to decrease with an increase in intracellular [Ca2+] and to be equal whether the compound was supplied extracellularly or intracellularly from the cell membrane. After 100 nM apamin was applied, HEK293 cells transfected with hSK3 channels were inhibited by 80%, and by 300 nM NS8593, by 75%. By contrast, at 300 nM, NS8593 reduced the activity of mutant channels by 45%. Consequently, even with a Kd value of 0.43 µM, which is 4-fold greater than that of the wild-type hSK3 channel (Kd of 0.10 µM), NS8593 is still active on the apamin-insensitive SK3 channel. Given that the level of SK3 channel activation determines NS8593's potency, the decreased potency could be the result of the mutant channel's increased apparent Ca2+ sensitivity. At a 500 nM Ca2+ concentration, the efficacy of NS8593 dropped three times, from 0.67 µM to 2.2 µM, in line with whole-cell investigations [1].
In vitro, NS8593 HCl is a potent and selective inhibitor of SK channels. It reversibly inhibits SK3-mediated currents with a Kd of 77 nM. It inhibits all SK1-3 subtypes in a calcium-dependent manner, with Kd values of 0.42 μM for SK1, 0.60 μM for SK2, and 0.73 μM for SK3 in the presence of 0.5 μM calcium. The compound does not affect intermediate-conductance (IK) or large-conductance (BK) calcium-activated potassium channels. The compound's activity is typically measured using electrophysiological recordings (e.g., patch-clamp) in cells expressing SK1, SK2, or SK3 channels. In these assays, NS8593 HCl is applied to cells, and the amplitude of SK-mediated currents is measured in the presence of various concentrations of calcium. The Kd values are determined from dose-response curves. |
| ln Vivo |
In C57Bl/6 mice, NS8593 (compound 14) administered intravenously at doses of 3 and 10 mg/kg has the ability to modify the rate and pattern of dopaminergic neuron firing [1].
In vivo, NS8593 HCl is used as a pharmacological tool to study the role of SK channels in various physiological and pathological processes. By inhibiting SK channels, NS8593 HCl reduces the afterhyperpolarization that follows action potentials, thereby increasing neuronal excitability. The compound's selectivity for SK channels over IK and BK channels makes it a valuable tool for dissecting the specific roles of SK channels in neuronal function, smooth muscle contraction, and other processes. While specific in vivo efficacy data for NS8593 HCl are not extensively detailed in the available literature, its mechanism of action suggests that it would be effective in modulating neuronal excitability and muscle tone. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for NS8593 HCl are not conventional enzyme inhibition studies, as the compound is a negative modulator of ion channels rather than an enzyme inhibitor. Instead, the primary assays involve electrophysiological recordings using patch-clamp or two-electrode voltage clamp techniques in cells expressing SK1, SK2, or SK3 channels. In these assays, NS8593 HCl is applied to cells, and the amplitude of SK-mediated currents is measured in the presence of various concentrations of calcium. The Kd values for SK1 (0.42 μM), SK2 (0.60 μM), and SK3 (0.73 μM) are determined from dose-response curves. Radioligand binding studies using channel-specific ligands can also be performed to assess the compound's binding affinity and to confirm its negative modulatory mechanism of action.
|
| Cell Assay |
In vitro cellular assays for NS8593 HCl are conducted in cell lines expressing SK1, SK2, or SK3 channels, such as HEK293 cells or neuronal cell lines. Cells are treated with varying concentrations of NS8593 HCl, and SK channel activity is assessed using calcium imaging, fluorescent membrane potential dyes, or electrophysiological recordings. The compound's ability to inhibit SK-mediated currents is quantified by measuring the decrease in current amplitude or the shift in the calcium dose-response curve. These assays confirm that NS8593 HCl engages its target in a cellular context and produces the expected inhibition of SK channel activity.
|
| Animal Protocol |
In vivo animal studies for NS8593 HCl would typically be conducted in animal models of neurological or cardiovascular diseases where SK channels are implicated. Animals would be administered the compound, and outcomes would be assessed based on the specific disease model. For example, in models of epilepsy, the compound's ability to increase neuronal excitability could be assessed by measuring seizure frequency and severity. In models of ataxia, the compound's effects on motor function could be assessed using behavioral tests. These studies would confirm that NS8593 HCl is effective in vivo and provide information about its therapeutic potential.
|
| ADME/Pharmacokinetics |
Pharmacokinetic properties of NS8593 HCl indicate that it has a molecular weight of 299.80 and a molecular formula of C18H17F3N4O3S·HCl. The compound is soluble in DMSO, facilitating its use in in vitro assays and formulation for in vivo administration. For storage, the powder should be kept under appropriate conditions to maintain stability. The compound's purity is typically ≥98%, ensuring high quality and reproducibility in experimental studies.
|
| Toxicity/Toxicokinetics |
The toxicological profile of NS8593 HCl is primarily derived from its use as a research compound in preclinical studies. As a SK channel inhibitor, potential on-target effects could include changes in neuronal excitability, muscle tone, and cardiovascular function, given the roles of SK channels in these systems. Comprehensive toxicology studies would be required for therapeutic development, including assessments of neurological, cardiovascular, and muscle function.
|
| References |
|
| Additional Infomation |
NS8593 HCl is a potent and selective inhibitor of small conductance calcium-activated potassium (SK) channels. It has Kd values of 0.42 μM for SK1, 0.60 μM for SK2, and 0.73 μM for SK3 in the presence of 0.5 μM calcium. NS8593 HCl reversibly inhibits SK3-mediated currents with a Kd of 77 nM. The compound does not affect IK or BK channels. NS8593 HCl is not approved for clinical use and is available from research chemical suppliers for preclinical studies.
|
| Molecular Formula |
C17H18CLN3
|
|---|---|
| Molecular Weight |
299.7979
|
| Exact Mass |
299.119
|
| CAS # |
875755-24-1
|
| Related CAS # |
875755-39-8;875755-24-1 (HCl);
|
| PubChem CID |
71311765
|
| Appearance |
White to off-white solid powder
|
| LogP |
4.276
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
2
|
| Rotatable Bond Count |
2
|
| Heavy Atom Count |
21
|
| Complexity |
332
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
C1C[C@H](C2=CC=CC=C2C1)NC3=NC4=CC=CC=C4N3.Cl
|
| InChi Key |
VWEKCDTXUUPBNA-PFEQFJNWSA-N
|
| InChi Code |
InChI=1S/C17H17N3.ClH/c1-2-8-13-12(6-1)7-5-11-14(13)18-17-19-15-9-3-4-10-16(15)20-17;/h1-4,6,8-10,14H,5,7,11H2,(H2,18,19,20);1H/t14-;/m1./s1
|
| Chemical Name |
N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-benzimidazol-2-amine;hydrochloride
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~83.33 mg/mL (~277.95 mM)
H2O : ~1 mg/mL (~3.34 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.94 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (6.94 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (6.94 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.3356 mL | 16.6778 mL | 33.3556 mL | |
| 5 mM | 0.6671 mL | 3.3356 mL | 6.6711 mL | |
| 10 mM | 0.3336 mL | 1.6678 mL | 3.3356 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
