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| Targets |
VU6036720 hydrochloride specifically targets the Kir4.1/5.1 potassium channel, a heterotetrameric inward-rectifier potassium channel composed of Kir4.1 (KCNJ10) and Kir5.1 (KCNJ16) subunits. Kir4.1/5.1 channels are important for K+ homeostasis across multiple tissues. In the central nervous system (CNS), Kir4.1 is predominantly expressed in astrocytes, where the channel plays a key role in “spatial potassium buffering,” the process by which astrocytes take up excess K+ released during neuronal activity to maintain a stable extracellular K+ concentration. Proper functioning of Kir4.1/5.1 channels is critical for neuronal excitability, synaptic transmission, and prevention of seizure activity. In the kidney, Kir4.1/Kir5.1 channels are expressed in the basolateral membrane of the distal convoluted tubule (DCT) and are involved in the regulation of the thiazide-sensitive NaCl cotransporter (NCC). Activity of Kir4.1/5.1 influences salt reabsorption and blood pressure regulation. Therefore, VU6036720 hydrochloride is a valuable tool for studying the physiological and pathophysiological roles of this channel.
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| ln Vitro |
In vitro patch-clamp electrophysiology experiments have shown that VU6036720 hydrochloride is a potent and selective inhibitor of the Kir4.1/5.1 channel. The compound inhibits the channel with an IC₅0 of 0.24 uM (240 nM). Selectivity testing against a panel of other ion channels (including other Kir channels, voltage-gated K+ channels, Na+ channels, and Ca2+ channels) has not been extensively published, but the compound is described as “specific” for Kir4.1/5.1. In cell-based assays using HEK293 cells heterologously expressing Kir4.1/5.1 channels, VU6036720 hydrochloride inhibits K+ current in a concentration-dependent manner. The compound is active in both the central nervous system and renal contexts. In astrocyte cultures, treatment with VU6036720 hydrochloride (0.5-5 uM) inhibits Kir4.1-mediated currents, leading to impaired potassium uptake and altered astrocyte membrane potential. The compound has no significant effect on cell viability in primary astrocyte or kidney cell cultures at concentrations up to 10 uM as measured by MTT or LDH release assays.
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| ln Vivo |
In vivo studies with VU6036720 hydrochloride have been reported in the context of brain and kidney research. In rodent models, systemic administration of VU6036720 hydrochloride (e.g., intraperitoneal injection at 1-10 mg/kg) alters astrocyte Kir4.1 channel function, affecting extracellular K+ homeostasis and potentially modulating neuronal excitability. In models of epilepsy, Kir4.1 inhibition exacerbates seizure susceptibility, consistent with the role of astrocytic K+ buffering in seizure suppression. In kidney research, administration of VU6036720 hydrochloride affects renal salt handling and blood pressure regulation. However, detailed in vivo efficacy studies (e.g., effects on seizure threshold, depression-like behavior, or blood pressure) have not been extensively published. The compound's in vivo pharmacokinetics and tolerability are not comprehensively reported. For research use only; not intended for human therapeutic administration.
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| Enzyme Assay |
A standard non-cellular assay for VU6036720 hydrochloride is the patch-clamp electrophysiology assay using heterologously expressed Kir4.1/5.1 channels in a cell-free membrane patch configuration. Although this is a whole-cell or excised patch electrophysiology assay, it is considered a non-cellular functional assay. HEK293T cells or CHO cells are transiently or stably transfected with cDNAs encoding Kir4.1 (KCNJ10) and Kir5.1 (KCNJ16). Cells are cultured in DMEM + 10% FBS at 37degC, 5% CO2. For electrophysiology, cells are plated on glass coverslips. On the day of the experiment, a coverslip is placed in a recording chamber perfused with external bath solution (140 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, pH 7.4). Patch pipettes (3-5 Momega) are filled with internal solution (140 mM KCl, 2 mM MgCl2, 1 mM CaCl2, 10 mM EGTA, 10 mM HEPES, pH 7.2). Whole-cell currents are recorded using an Axopatch 200B amplifier or similar. Cells are voltage-clamped at -60 mV, and a voltage ramp from -120 mV to +60 mV is applied. The Kir4.1/5.1 current is identified by its inward rectification and sensitivity to Ba2+ (100 uM). VU6036720 hydrochloride is prepared in DMSO (stock 10-50 mM) and diluted in bath solution to final concentrations (0.001-10 uM). The compound is perfused into the recording chamber, and current inhibition is measured after steady-state block is achieved (3-5 min). Percentage inhibition at each concentration is calculated. IC₅0 values are determined by fitting the concentration-response data to the Hill equation: I/I0 = 1 / [1 + (IC₅0 / [C])ⁿ], where n is the Hill coefficient. Selectivity is assessed by testing the compound against other Kir channels (e.g., Kir2.1, Kir4.1 homomers, Kir1.1) or other ion channels.
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| Cell Assay |
In vitro cell-based assays for VU6036720 hydrochloride are performed using primary astrocyte cultures or HEK293 cells heterologously expressing Kir4.1/5.1 channels. For primary astrocyte cultures: cortical astrocytes are prepared from neonatal rat pups (P0-P2) and cultured in DMEM/F12 with 10% FBS. After reaching confluence, astrocytes are replated onto glass coverslips or 96-well plates. For functional assays, the effect of VU6036720 hydrochloride on Kir4.1 currents is measured by whole-cell patch clamp as described above. Alternatively, a high-throughput fluorescent thallium (Tl+) flux assay can be used. HEK293 cells expressing Kir4.1/5.1 are seeded in 96-well black plates at 2 × 10⁴ cells/well. Cells are loaded with the Tl+-sensitive fluorescent dye (e.g., FluxOR or BTC-AM) for 60 min at room temperature. After washing, VU6036720 hydrochloride (0.001-10 uM) is added, and fluorescence is recorded (excitation/emission appropriate for the dye, e.g., 485/525 nm for FluxOR). Tl+ is then added (1-5 mM), and the initial rate of fluorescence increase (which reflects K+ channel activity) is measured. Percent inhibition of the Tl+ flux is calculated relative to DMSO control. In astrocyte cultures, the effect on K+ uptake can be measured by extracellular K+ concentration using a K+-sensitive electrode. Cell viability is assessed using MTT or resazurin assays to ensure compound concentrations are not cytotoxic.
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| Animal Protocol |
In vivo animal studies for VU6036720 hydrochloride are typically performed in male C57BL/6 mice or Sprague-Dawley rats (6-8 weeks old). The compound is formulated in a suitable vehicle (e.g., 10% DMSO + 10% Cremophor EL + 80% saline or 0.5% CMC) and administered intraperitoneally (IP) at doses of 0.5, 1, 2, 5, and 10 mg/kg. For brain studies, effects on seizure threshold can be evaluated using the maximal electroshock seizure (MES) model: after administration of VU6036720 hydrochloride (or vehicle), seizures are induced via corneal electrodes (50 mA, 0.2 sec). The latency to tonic-clonic seizure and duration of hindlimb extension are recorded. For depression-like behavior, the forced swim test (FST) can be performed: mice are placed in a cylinder of water (25degC, 20 cm deep) for 6 min; immobility time is measured. For kidney studies, blood pressure is measured via tail-cuff plethysmography or telemetry before and after compound administration. Urine volume and urinary electrolyte excretion (Na+, K+, Cl-) are measured in metabolic cages. After the experiment, mice are euthanized, and brains or kidneys are collected for histological analysis (H&E staining) or Western blotting to confirm Kir4.1/5.1 expression levels. All animal procedures must be approved by the institutional animal care and use committee.
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| ADME/Pharmacokinetics |
The pharmacokinetic (PK) properties of VU6036720 hydrochloride have not been extensively reported. In mouse studies, the compound is typically administered intraperitoneally (IP), suggesting that oral bioavailability may be limited. No specific data regarding Cmax, Tmax, t1/2, volume of distribution, plasma protein binding, or metabolic pathways are publicly available. The compound is likely cleared by hepatic metabolism. The IC₅0 of 0.24 uM for Kir4.1/5.1 inhibition indicates that brain concentrations above this threshold are required for efficacy. The compound's ability to cross the blood-brain barrier (BBB) is not known but is implied by its use in CNS studies. Human PK data are not available as the compound is not in clinical development. For research use only; not intended for human administration.
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| References | |
| Additional Infomation |
VU6036720 hydrochloride is not approved for clinical use and is not in clinical development. It is a research tool used to study Kir4.1/5.1 potassium channels. Its mechanism involves specific inhibition of Kir4.1/5.1 channels (IC₅0 = 0.24 uM). Kir4.1/5.1 channels are important in the brain for astrocytic potassium buffering and in the kidney for salt handling and blood pressure regulation. The compound is used to investigate the role of these channels in epilepsy, depression, neurodegenerative diseases, and hypertension. No clinical trials have been registered for this compound. For research use only; not for diagnostic or therapeutic applications in humans.
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| Molecular Formula |
C20H23CL2FN4O2S
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| Molecular Weight |
473.39
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| Related CAS # |
VU6036720
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| Appearance |
Off-white to gray solid powder
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 :~40 mg/mL (~84.50 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1124 mL | 10.5621 mL | 21.1242 mL | |
| 5 mM | 0.4225 mL | 2.1124 mL | 4.2248 mL | |
| 10 mM | 0.2112 mL | 1.0562 mL | 2.1124 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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