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| Targets |
The primary targets of NS13001 are the SK2 and SK3 subtypes of small conductance calcium-activated potassium (SK/KCa2) channels. It acts as a selective positive allosteric modulator of these channels, with EC50 values of 1.8 μM for SK2 and 0.14 μM for SK3. Positive allosteric modulation means that NS13001 enhances the activity of the channels in the presence of calcium, increasing the amplitude and duration of the afterhyperpolarization that follows action potentials. This modulation of SK channel activity is thought to reduce neuronal hyperexcitability, which is a key feature of cerebellar ataxia. NS13001 acts as an inhibitor of potassium channels (KcsA), which are vital for maintaining cellular excitability and signaling. The compound's selectivity for SK2 and SK3 over other channel subtypes makes it a valuable tool for studying the specific roles of these channels in neuronal function and disease.
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| ln Vitro |
In vitro, NS13001 is a selective positive allosteric modulator of SK2 and SK3 channels. It has EC50 values of 1.8 μM for SK2 and 0.14 μM for SK3. The compound's activity is typically measured using electrophysiological techniques such as patch-clamp recordings in cells expressing SK2 or SK3 channels. In these assays, NS13001 enhances the calcium sensitivity of the channels, increasing the amplitude of the SK-mediated currents. The compound's selectivity for SK2 and SK3 over other channel subtypes is confirmed by testing its activity against SK1, IK, and BK channels. NS13001's potent activity at SK3 (EC50 = 0.14 μM) suggests that it may be particularly effective at modulating SK3-mediated effects in neurons and other cell types.
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| ln Vivo |
In vivo, NS13001 is orally active and holds promise as a potential therapeutic agent for the treatment of spinocerebellar ataxia type 2 (SCA2) and possibly other cerebellar ataxias. SCA2 is a progressive neurodegenerative disorder characterized by cerebellar dysfunction, leading to gait ataxia, dysarthria, and oculomotor abnormalities. The positive modulation of SK channels is thought to enhance the afterhyperpolarization that follows action potentials, thereby reducing neuronal hyperexcitability, which is a key feature of cerebellar ataxia. The compound's oral bioavailability makes it a convenient tool for in vivo studies and a promising candidate for therapeutic development. While specific in vivo efficacy data for NS13001 in animal models of SCA2 are not extensively detailed in the available literature, its mechanism of action and in vitro activity suggest that it would be effective in reducing cerebellar ataxia symptoms.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for NS13001 are not conventional enzyme inhibition studies, as the compound is a positive allosteric 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 SK2 or SK3 channels. In these assays, NS13001 is applied to cells, and the amplitude of SK-mediated currents is measured in the presence of various concentrations of calcium. The EC50 values for SK2 (1.8 μM) and SK3 (0.14 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 allosteric mechanism of action.
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| Cell Assay |
In vitro cellular assays for NS13001 are conducted in cell lines expressing SK2 or SK3 channels, such as HEK293 cells or neuronal cell lines. Cells are treated with varying concentrations of NS13001, and SK channel activity is assessed using calcium imaging or electrophysiological recordings. The compound's ability to enhance SK-mediated currents is quantified by measuring the increase in current amplitude or the shift in the calcium dose-response curve. These assays confirm that NS13001 engages its target in a cellular context and produces the expected enhancement of SK channel activity.
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| Animal Protocol |
In vivo animal studies for NS13001 would typically be conducted in mouse models of spinocerebellar ataxia type 2 (SCA2), such as transgenic mice expressing mutant ataxin-2. Animals would be administered the compound orally, and motor function would be assessed using behavioral tests such as the rotarod, gait analysis, and open field test. The compound's effects on cerebellar Purkinje cell firing and neuronal excitability could be assessed using in vivo electrophysiological recordings. Histological examination of cerebellar tissue would be performed to assess Purkinje cell survival and morphology. These studies would confirm that NS13001 is effective in vivo and support its continued development for the treatment of cerebellar ataxias.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of NS13001 indicate that it has a molecular weight of 353.81 and a molecular formula of C17H16ClN7. The compound is orally active, enabling convenient administration for in vivo studies. It is soluble in DMSO, facilitating its use in in vitro assays and formulation for in vivo administration. For storage, the powder should be kept at 0-4°C for short term or -20°C for long term. The compound's purity is typically >98%, ensuring high quality and reproducibility in experimental studies.
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| Toxicity/Toxicokinetics |
The toxicological profile of NS13001 is primarily derived from its use as a research compound in preclinical studies. As a positive modulator of SK channels, 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. However, NS13001 is primarily used as a research tool and has not yet advanced to clinical development.
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| References | |
| Additional Infomation |
NS13001 is an orally active, selective positive allosteric modulator of SK2 and SK3 channels. It is also known as N-(4-Chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-9-methyl-9H-purin-6-amine. The compound has EC50 values of 1.8 μM for SK2 and 0.14 μM for SK3. NS13001 holds promise as a potential therapeutic agent for the treatment of spinocerebellar ataxia type 2 (SCA2) and possibly other cerebellar ataxias. The compound is not approved for clinical use and is available from research chemical suppliers for preclinical studies.
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| Molecular Formula |
C17H16CLN7
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| Molecular Weight |
353.81
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| Exact Mass |
353.116
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| CAS # |
1063331-94-1
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| PubChem CID |
44472568
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| Appearance |
White to light yellow solid powder
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| LogP |
3.635
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
25
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| Complexity |
458
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
DVQOPNIPUIOXHU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H16ClN7/c1-10-8-11(2)25(23-10)17-21-15(14-16(22-17)24(3)9-19-14)20-13-6-4-12(18)5-7-13/h4-9H,1-3H3,(H,20,21,22)
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| Chemical Name |
N-(4-chlorophenyl)-2-(3,5-dimethylpyrazol-1-yl)-9-methylpurin-6-amine
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| Synonyms |
NS-13001; NS 13001; NS13001
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~282.64 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (2.35 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 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: 0.83 mg/mL (2.35 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 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: ≥ 0.83 mg/mL (2.35 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 | 2.8264 mL | 14.1319 mL | 28.2638 mL | |
| 5 mM | 0.5653 mL | 2.8264 mL | 5.6528 mL | |
| 10 mM | 0.2826 mL | 1.4132 mL | 2.8264 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.
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