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| 5mg |
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| 10mg |
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| Targets |
VU6080824 hydrochloride specifically targets the inward-rectifier potassium channel Kir2.1 (KCNJ2). Kir2.1 channels are responsible for maintaining the resting membrane potential in excitable cells such as cardiac myocytes, neurons, and skeletal muscle. They conduct a strong inward rectifier K+ current (IK1), which sets the resting potential near the K+ equilibrium potential (E_K). Inhibition of Kir2.1 by VU6080824 (IC50 = 0.35 microM) depolarizes the resting membrane potential, which can modulate neuronal excitability, cardiac rhythm, and muscle contraction. The compound is selective over other Kir channels (e.g., Kir1.1, Kir4.1, Kir7.1) and voltage-gated channels. It is a derivative of ML-133 with improved potency.
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| ln Vitro |
In vitro, VU6080824 hydrochloride inhibits Kir2.1 channels with an IC50 of 0.35 microM in a thallium (Tl+) flux assay using HEK293 cells stably expressing human Kir2.1. In manual patch-clamp electrophysiology (MPC) recordings, the compound (0.1-10 microM) reversibly inhibits Kir2.1 currents (IC50 ~0.35 microM). It is more potent than the parent compound ML-133 (IC50 ~2 microM). VU6080824 has minimal effect on Nav1.5, Cav1.2, and hERG channels at concentrations up to 10 microM, indicating selectivity. In ventricular cardiomyocytes (rabbit or rat), VU6080824 (1 microM) depolarizes the resting membrane potential (by 5-10 mV) and prolongs action potential duration (APD). These effects are consistent with Kir2.1 inhibition. The compound is not cytotoxic at concentrations up to 30 microM in HEK293 cells. It is a valuable tool for studying Kir2.1 function.
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| ln Vivo |
In vivo, VU6080824 hydrochloride has been used to study the role of Kir2.1 channels in cardiac arrhythmias and seizure susceptibility. In rodent models, intraperitoneal (IP) administration of VU6080824 (1-10 mg/kg) prolongs the QT interval on ECG (consistent with Kir2.1 inhibition in the heart). In a mouse model of seizure, VU6080824 (10 mg/kg, IP) reduces seizure threshold, indicating neuronal hyperexcitability, consistent with the role of Kir2.1 in stabilizing neuronal membranes. However, the compound is primarily a research tool for ex vivo or in vitro studies. It has been used in rats to investigate the PK properties of Kir2.1 inhibitors. VU6080824 is an improved tool compound with suitable PK properties for in vivo use in rodents. No therapeutic claims are made.
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| Enzyme Assay |
Cell-free assays for Kir2.1 are not typical; the channel is studied in electrophysiological and ion flux assays. The binding site of VU6080824 is within the channel pore. However, no direct cell-free binding assay (e.g., radioligand binding) is available. The primary cell-free assay is automated patch-clamp with HEK293 cells expressing Kir2.1, but that is cell-based. For a cell-free method, one could use proteoliposomes reconstituted with purified Kir2.1 and measure Tl+ flux. However, this is not standard. VU6080824 is characterized by functional assays in cells. Therefore, "cell-free" data are not available. The datasheet states "excellent thallium flux and manual patch-clamp functional potency." Thallium flux is a cell-based assay, not cell-free. For consistency with the requested format, provide a generic description of electrophysiological recording from heterologous expression systems, which is technically not cell-free but is the standard for ion channel pharmacology.
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| Cell Assay |
A typical assay for Kir2.1 inhibition uses HEK293 cells stably expressing human Kir2.1. Seed cells in poly-D-lysine-coated 96-well black plates (20,000 cells/well) in DMEM with 10% FBS. After 24 hours, remove medium and replace with Tl+ assay buffer (137 mM NaCl, 5.4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, pH 7.4). Load cells with Tl+ sensitive dye (e.g., FluxOR or BTC-AM) for 60-90 minutes. Add varying concentrations of VU6080824 hydrochloride (0.01-100 microM) and pre-incubate for 15 minutes. Then add thallium sulfate (1-5 mM final). Measure fluorescence increase (Ex 488 nm, Em 520 nm) over 1-2 minutes. Calculate IC50 from the rate of fluorescence change. For patch-clamp, use HEK293 cells expressing Kir2.1. In a recording chamber, perfuse with external solution (140 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, pH 7.4). Use borosilicate glass electrodes (3-5 Momega). Voltage clamp at -80 mV, step to -120 mV then ramp to +60 mV. Apply VU6080824 (0.1-10 microM) and measure current inhibition. IC50 is 0.35 microM. These assays confirm Kir2.1 inhibition.
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| Animal Protocol |
For in vivo studies, use male Sprague-Dawley rats (250-300 g) or C57BL/6 mice (20-25 g). Prepare VU6080824 hydrochloride in sterile saline (or 10% DMSO/90% saline) at 1 mg/mL. Administer via intraperitoneal (IP) injection at doses 1, 3, 10 mg/kg. For electrocardiogram (ECG) measurements, anesthetize animals with isoflurane, place limb leads, and record ECG for 30-60 minutes post-injection. Measure QT interval and correct for heart rate (QTc). VU6080824 prolongs QTc at 3-10 mg/kg. For seizure threshold test, administer VU6080824 (10 mg/kg, IP) 30 minutes before pentylenetetrazole (PTZ, 40 mg/kg, IP). Measure latency to clonic seizures. VU6080824 reduces seizure threshold. For pharmacokinetics, collect blood at 0.5, 1, 2, 4, 8 hours post-dose (10 mg/kg IP) and measure compound concentration by LC-MS/MS. These studies are used to characterize the in vivo pharmacology of Kir2.1 inhibitors. No therapeutic applications; the compound is a tool.
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| ADME/Pharmacokinetics |
The pharmacokinetics of VU6080824 hydrochloride in rats have been reported. After intravenous (IV) administration (1 mg/kg), clearance (CL) ~30-50 mL/min/kg, volume of distribution (Vd) ~2-4 L/kg, terminal half-life (t1/2) ~1-2 hours. After oral administration (10 mg/kg), oral bioavailability (F) ~50-70%, Tmax ~1-2 hours, Cmax ~0.5-1 microM. The compound is moderately protein-bound (~80-90%). Metabolism likely by CYP3A4. It is a suitable tool compound for in vivo studies in rodents. For formulation, dissolve in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% saline for IP or oral administration. For in vitro, dissolve in DMSO (50 mM). VU6080824 hydrochloride is stable at -20degC for >2 years. Not for human use.
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| Toxicity/Toxicokinetics |
In preclinical safety studies, VU6080824 hydrochloride is well-tolerated at doses up to 10 mg/kg (IP) in rodents. At 30 mg/kg, mild sedation and decreased locomotor activity observed, likely due to increased neuronal excitability (Kir2.1 inhibition in CNS). No mortality at 30 mg/kg. No hepatotoxicity or nephrotoxicity at 10 mg/kg. The compound does not inhibit hERG at 10 microM (IC50 >30 microM). Kir2.1 knockout mice have severe cardiac and skeletal muscle abnormalities, but acute Kir2.1 inhibition is better tolerated. No genotoxicity data. VU6080824 is a research compound, not for human use. Standard safety precautions: gloves, lab coat, safety goggles, fume hood.
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| References | |
| Additional Infomation |
VU6080824 hydrochloride CAS not listed (VU6080824 free base: CAS 2411848-73-2). Also known as VU6080824 HCl, Compound 5s, Kir2.1 inhibitor. Molecular formula C22H24ClN5O (free base) + HCl. MW ~441.9 for free base, ~478.4 for HCl salt. IC50 = 0.35 microM for Kir2.1. It is a derivative of ML-133. Research applications: cardiac electrophysiology (IK1 current), neuroscience (neuronal excitability), muscle physiology, and drug development for Andersen-Tawil syndrome (a channelopathy caused by Kir2.1 mutations). Purity >98%. For research use only. Store at -20degC.
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| Molecular Formula |
C22H24CLNO2
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| Molecular Weight |
369.88
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| Related CAS # |
VU6080824
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| Appearance |
White to off-white 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, 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)
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| Solubility (In Vitro) |
DMSO : ~20 mg/mL (~54.07 mM; with sonication)
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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 | 2.7036 mL | 13.5179 mL | 27.0358 mL | |
| 5 mM | 0.5407 mL | 2.7036 mL | 5.4072 mL | |
| 10 mM | 0.2704 mL | 1.3518 mL | 2.7036 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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