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| Targets |
VU0810464 targets G protein-gated inwardly rectifying potassium channels (GIRK), also known as Kir3 channels. These channels moderate the activity of excitable cells and have been implicated in neurological disorders and cardiac arrhythmias. VU0810464 specifically activates neuronal GIRK1/2 (Kir3.1/3.2) heterotetramers with enhanced selectivity over cardiac GIRK1/4 (Kir3.1/3.4) channels. By activating GIRK channels, the compound increases potassium conductance, hyperpolarizes neurons, and reduces neuronal excitability. This mechanism is being explored for therapeutic applications in neurological and neuropsychiatric disorders including Alzheimer's disease, schizophrenia, and Parkinson's disease.
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| ln Vitro |
In SAN and HPC cells, VU0810464 (0, 0.1, 0.3, 1, 3, 10, 30 μM) generated concentration-dependent current response curves. Furthermore, compared to the control SAN unit, VU0810464 had nine times the potency to activate Kir3 channels in neurons[2].
In vitro, VU0810464 activates neuronal GIRK1/2 channels with an EC₅₀ of 165 nM and GIRK1/4 channels with an EC₅₀ of 720 nM. In whole-cell electrophysiology assays using SAN and hippocampal neurons, the compound generates concentration-dependent current responses at concentrations ranging from 0.1 to 30 μM. Compared to the prototypical GIRK activator ML297, VU0810464 exhibits nine-fold greater potency for activating Kir3 channels in neurons. The compound demonstrates improved selectivity for neuronal versus cardiac Kir3 channels and shows enhanced brain penetration. VU0810464 displays no significant cytotoxicity at concentrations up to 10 μM in neuronal cultures. |
| ln Vivo |
Male C57BL/6J mice treated with VU0810464 (ip; 30 mg/kg, 10 mg/kg, 30 mg/kg; 30 min pretreatment) showed a dose-dependent decrease in the SIH response. VU0810464 (10 mg/kg) decreased the SIH response in wild-type mice but showed no impact in Kcnj3−/− animals, suggesting that it may work through Kir3 channel activation [2]. Compared to ML297 (Kp,uu = 0.32) VU0810464 (ip; 30 mg/kg; 15, 30, 45, or 60 minutes postinjection) demonstrated good brain distribution (Kp,uu = 0.83). According to PK tests, VU0810464 is rapidly eliminated, having a 20-minute half-life in the brain and plasma [2].
In vivo, VU0810464 (10 and 30 mg/kg, intraperitoneal) produces dose-dependent reduction of stress-induced hyperthermia (SIH) in male C57BL/6J mice. This effect is Kir3-dependent, as VU0810464 showed no impact in Kcnj3 (Girk1) knockout mice. In an Alzheimer's disease mouse model with intracerebroventricular amyloid-β oligomer injection, VU0810464 normalized hippocampal long-term potentiation and improved object location memory. The compound reduced Aβ oligomer-induced hippocampal hyperexcitability. In healthy mice, low-dose VU0810464 had no significant effect on synaptic plasticity or memory, while higher doses impaired both processes. ML297, but not VU0810464, decreased anxiety-related behavior in the elevated plus maze test. |
| Enzyme Assay |
In vitro enzyme/receptor binding (non-cellular) assays for VU0810464 typically involve thallium flux assays using HEK293 cells expressing GIRK1/2 or GIRK1/4 channels. Membrane preparations from transfected cells are incubated with varying concentrations of the compound, and thallium influx through activated GIRK channels is measured using fluorescent indicators. EC₅₀ values are calculated from concentration-response curves. Whole-cell patch-clamp electrophysiology on isolated membrane patches or heterologously expressed channels measures GIRK channel activation directly. Selectivity for neuronal versus cardiac Kir3 channels is assessed by comparing activity on Kir3.1/3.2 versus Kir3.1/3.4 heterotetramers. Brain penetration is evaluated using unbound brain-to-plasma partition coefficient (Kp,uu) measurements.
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| Cell Assay |
In vitro cellular experiments with VU0810464 are performed using primary neuronal cultures or HEK293 cells heterologously expressing GIRK channels. Cells are cultured in appropriate media and treated with varying concentrations of VU0810464 (0.1–30 μM). GIRK channel activation is assessed by whole-cell patch-clamp electrophysiology, measuring potassium currents in response to compound application. In SAN and hippocampal neurons, concentration-dependent current response curves are generated. For studies of synaptic plasticity, hippocampal slices are treated with VU0810464 and long-term potentiation is measured. Cell viability is assessed via LDH release or MTT assays. Neurons are maintained at 37°C in 5% CO₂ with appropriate culture media supplements.
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| Animal Protocol |
Animal/Disease Models: Male C57BL/6J mice, Kcnj3−/− female and male C57BL/6J mice
Doses: 10mg/kg; 30mg/kg Route of Administration: intraperitoneal (ip) injection Experimental Results: Reduce stress-induced hyperthermia (SIH), This is a physiological test of anxiolytic efficacy in wild-type mice but has no effect on Kcnj3 (Girk1) −/− mice. In vivo animal studies with VU0810464 have been conducted in mouse models. Male C57BL/6J mice receive VU0810464 via intraperitoneal injection at doses of 10 or 30 mg/kg, with 30-minute pretreatment. Stress-induced hyperthermia is measured as a physiological readout of anxiolytic efficacy; the compound reduces SIH in a dose-dependent manner. In Alzheimer's disease models, mice receive intracerebroventricular injection of amyloid-β oligomers, followed by VU0810464 treatment. Hippocampal-dependent spatial memory is assessed using object location memory tasks, and synaptic plasticity is measured via long-term potentiation in hippocampal slices. Kcnj3 (Girk1) knockout mice are used to confirm Kir3-dependent mechanism of action. Pharmacodynamic markers include neuronal excitability and network activity measures. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of VU0810464 indicate rapid absorption and distribution following intraperitoneal administration. The compound demonstrates good brain penetration with an unbound brain-to-plasma partition coefficient (Kp,uu) of 0.83, compared to 0.32 for ML297. VU0810464 is rapidly eliminated, with a half-life of approximately 20 minutes in both brain and plasma. The compound is soluble in DMSO at ≥120 mg/mL. Storage recommendations: powder at -20°C for up to 3 years or 4°C for 2 years; in solution at -80°C for 6 months or -20°C for 1 month. The compound should be protected from light and moisture. Purity is typically ≥98%.
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| Toxicity/Toxicokinetics |
VU0810464 has been evaluated in preclinical safety studies and appears well-tolerated at therapeutic doses. In mice, intraperitoneal administration at 30 mg/kg produced no overt signs of toxicity. The compound's mechanism of action—enhancing neuronal potassium conductance—is expected to reduce hyperexcitability without major off-target effects due to its selectivity for neuronal over cardiac GIRK channels. However, higher doses in healthy animals impaired hippocampal synaptic plasticity and memory, indicating a narrow therapeutic window. Standard safety precautions for handling research chemicals apply: use personal protective equipment (gloves, goggles, lab coat), avoid inhalation and skin contact, and work in a well-ventilated area. The compound is for research use only and is not approved for human therapeutic use.
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| References |
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| Additional Infomation |
VU0810464 (CAS 2126040-21-7) is a potent and selective non-urea activator of G protein-gated inwardly rectifying potassium channels (GIRK/Kir3). It displays nanomolar potency for neuronal GIRK1/2 (EC₅₀ = 165 nM) and GIRK1/4 (EC₅₀ = 720 nM) channels with improved brain penetration. The compound has been studied in preclinical models of Alzheimer's disease, where low-dose administration improved hippocampal-dependent synaptic plasticity and memory disrupted by amyloid-β oligomers. VU0810464 also reduces stress-induced hyperthermia in a Kir3-dependent manner. It represents a new class of Kir3 channel activator with enhanced selectivity for neuronal Kir3.1/3.2 channels and may be useful for probing the therapeutic potential of GIRK channel modulation in neurological disorders. Purity: ≥98%. Storage: powder at -20°C (3 years) or 4°C (2 years); solution at -80°C (6 months) or -20°C (1 month).
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| Molecular Formula |
C18H21CLFN3O
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| Molecular Weight |
349.830246686935
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| Exact Mass |
349.135
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| CAS # |
2126040-21-7
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| PubChem CID |
146014436
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| Appearance |
White to off-white solid powder
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| LogP |
4.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
24
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| Complexity |
433
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=C(C=CC(=C1)CC(NC1=CC(C)=NN1C1CCCCC1)=O)F
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| InChi Key |
HNJJARDABGKWSO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H21ClFN3O/c1-12-9-17(23(22-12)14-5-3-2-4-6-14)21-18(24)11-13-7-8-16(20)15(19)10-13/h7-10,14H,2-6,11H2,1H3,(H,21,24)
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| Chemical Name |
2-(3-chloro-4-fluorophenyl)-N-(2-cyclohexyl-5-methylpyrazol-3-yl)acetamide
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| Synonyms |
VU 0810464; VU-0810464
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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 : ≥ 250 mg/mL (~714.63 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8585 mL | 14.2927 mL | 28.5853 mL | |
| 5 mM | 0.5717 mL | 2.8585 mL | 5.7171 mL | |
| 10 mM | 0.2859 mL | 1.4293 mL | 2.8585 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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