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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| Targets |
The primary molecular target of (S)-Viloxazine Hydrochloride is the norepinephrine transporter (NET), as it is a selective norepinephrine reuptake inhibitor. By binding to the norepinephrine transporter, the compound inhibits the reuptake of norepinephrine, increasing its synaptic concentration and enhancing noradrenergic neurotransmission. This mechanism is responsible for its antidepressant and ADHD therapeutic effects. Viloxazine and its isomers are also described as multimodal serotonergic agents, suggesting that the S-isomer may interact with serotonin receptors or transporters in addition to the norepinephrine transporter. The S-isomer is likely the more pharmacologically active enantiomer of viloxazine, as the R-isomer has been reported to be less active. The compound may also bind to adrenergic receptors (α₁, α₂, β) and serotonergic receptors (5-HT receptors) with varying affinities, contributing to its overall pharmacological profile.
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| ln Vitro |
In vitro activity of (S)-Viloxazine Hydrochloride is primarily assessed through its ability to inhibit norepinephrine reuptake. In cell-based assays using cells expressing the human norepinephrine transporter (hNET), the compound inhibits [³H]norepinephrine uptake with an IC50 expected to be in the low nanomolar to micromolar range. As the more active enantiomer, the S-isomer is likely more potent than the R-isomer at inhibiting norepinephrine reuptake. The compound may also inhibit serotonin and dopamine reuptake, though with lower affinity than for norepinephrine, reflecting its selectivity for the norepinephrine transporter. In receptor binding assays, (S)-Viloxazine Hydrochloride may bind to various serotonin receptors (5-HT₁A, 5-HT₂A, 5-HT₂C, etc.) and adrenergic receptors with Ki values in the nanomolar to micromolar range. Its multimodal serotonergic profile suggests it may act as an agonist or antagonist at specific serotonin receptor subtypes.
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| ln Vivo |
In vivo activity of (S)-Viloxazine Hydrochloride is expected to be similar to that of racemic viloxazine, which has been used clinically as an antidepressant and for ADHD treatment. In animal models of depression (forced swim test, tail suspension test), the S-isomer would be expected to show antidepressant-like effects by increasing synaptic norepinephrine levels. In ADHD models such as the spontaneous hypertensive rat (SHR) model or the 5-choice serial reaction time task, the compound would be expected to improve attention and reduce hyperactivity. Dosing in animal studies would typically be in the range of 1-20 mg/kg administered orally or intraperitoneally. The S-isomer, being the more active enantiomer, may show greater efficacy than the R-isomer at equivalent doses. The compound's ability to cross the blood-brain barrier is essential for its central nervous system effects, and its distribution into the brain is likely efficient due to its moderate lipophilicity and molecular size.
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| Enzyme Assay |
For in vitro norepinephrine reuptake inhibition assays with (S)-Viloxazine Hydrochloride, the following protocol is used: HEK293 cells expressing human norepinephrine transporters (hNET) are maintained in DMEM with 10% FBS and antibiotics. For the assay, cells are seeded in 24-well plates at 200,000 cells/well and grown for 48 hours. The assay buffer is KRH buffer (120 mM NaCl, 4.7 mM KCl, 2.2 mM CaCl₂, 1.2 mM MgSO₄, 1.2 mM KH₂PO₄, 10 mM HEPES, 1 mM ascorbic acid, pH 7.4). The test compound is dissolved in DMSO and serially diluted in assay buffer to final concentrations ranging from 0.01 nM to 100 μM. Cells are pre-incubated with the compound for 10 minutes at 25°C, then [³H]norepinephrine (50 nM) is added and incubation continues for 10 minutes. The reaction is terminated by three washes with ice-cold buffer. Cells are lysed with 1% SDS and radioactivity is measured by scintillation counting. Nonspecific uptake is determined with 10 μM desipramine. IC50 values are calculated using nonlinear regression analysis of the dose-response data. Ki values can be calculated using the Cheng-Prusoff equation if the Km of the transporter for norepinephrine is known.
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| Cell Assay |
For in vitro cell-based assays with viloxazine isomers, the following typical protocol is used: SH-SY5Y neuroblastoma cells or PC12 cells are cultured in RPMI-1640 or DMEM with 10% FBS and antibiotics at 37°C in 5% CO₂. Cells are seeded in 96-well plates at 10,000-15,000 cells per well and allowed to attach overnight. The test compound is dissolved in DMSO and diluted in culture medium to final concentrations ranging from 0.01 to 100 μM. After 24-72 hours of treatment, cell viability is assessed using the MTT assay (0.5 mg/mL MTT for 4 hours, followed by solubilization and reading at 570 nm). For apoptosis assessment, cells are stained with Annexin V-FITC and PI and analyzed by flow cytometry. For neurotransmitter release studies, cells are loaded with [³H]norepinephrine and then stimulated with KCl or veratridine in the presence or absence of the test compound, and the released radioactivity is measured by scintillation counting. For receptor binding studies, membrane preparations are incubated with radiolabeled ligands and varying concentrations of the test compound, followed by filtration and scintillation counting.
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| Animal Protocol |
For in vivo animal studies with viloxazine isomers, the following general protocol is used: male C57BL/6 mice (6-8 weeks old, 20-25 g) or Sprague-Dawley rats (6-8 weeks old, 180-220 g) are housed under standard conditions with a 12-hour light/dark cycle and free access to food and water. The test compound is formulated in saline or 0.5% methylcellulose and administered orally at doses of 1, 3, 10, and 30 mg/kg (dosing volume 10 mL/kg for mice, 5 mL/kg for rats). For the forced swim test, mice are placed in a cylinder (25 cm height, 15 cm diameter) filled with water (25°C, 15 cm depth) for 6 minutes. The duration of immobility is scored during the last 4 minutes. For the tail suspension test, mice are suspended by the tail from a horizontal bar for 6 minutes and immobility time is recorded. For ADHD models, the 5-choice serial reaction time task is used to assess attention and impulsivity, or the spontaneous hypertensive rat model is used to assess hyperactivity. Blood and brain tissue samples are collected at various time points for pharmacokinetic analysis.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of (S)-Viloxazine Hydrochloride are expected to be similar to those of racemic viloxazine but may show stereoselective differences compared to the R-isomer. Viloxazine is well-absorbed after oral administration with a bioavailability of 80-90% in humans. The S-isomer may have different metabolic clearance rates compared to the R-isomer due to stereoselective metabolism by cytochrome P450 enzymes (particularly CYP2D6 and CYP3A4) and UDP-glucuronosyltransferases. The elimination half-life is approximately 2-5 hours in humans. Plasma protein binding is approximately 50-60%. The compound is distributed into tissues, including the brain, due to its ability to cross the blood-brain barrier. The volume of distribution is moderate (~1-2 L/kg). The compound is primarily eliminated via hepatic metabolism, with metabolites excreted in the urine. Stereoselective differences in pharmacokinetics between the R- and S-isomers could affect the overall therapeutic profile and should be characterized in comprehensive PK studies.
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| Toxicity/Toxicokinetics |
The toxicity profile of (S)-Viloxazine Hydrochloride is not separately characterized from that of racemic viloxazine. Racemic viloxazine has been used clinically for depression and ADHD, and its safety profile is well-established. Common side effects include gastrointestinal disturbances (nausea, vomiting), headache, drowsiness, dry mouth, and insomnia. Cardiovascular effects such as hypertension and tachycardia may occur, particularly at higher doses. Psychiatric effects including agitation, anxiety, and irritability have been reported. The S-isomer, being the more active enantiomer, may have a different adverse effect profile, potentially with either greater efficacy at lower doses (reducing side effects) or increased toxicity due to higher potency. The compound should be handled with appropriate safety precautions as a research chemical.
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| Additional Infomation |
(S)-Viloxazine Hydrochloride (CAS# 56287-61-7) is the S-isomer of viloxazine, a selective norepinephrine reuptake inhibitor (NRI) that can be used as an antidepressant. Racemic viloxazine (Qelbree, Vivalan, Emovit) received FDA approval in 2021 for ADHD treatment. The S-isomer has a molecular formula of C13H20ClNO3 and a molecular weight of 273.76 g/mol. Its unique ingredient identifier is 6X6CUH2JS9. The compound is also a multimodal serotonergic agent. Future research could focus on the stereoselective pharmacology of viloxazine enantiomers, exploring differences in target engagement, metabolic stability, and therapeutic outcomes to optimize the development of enantiomerically pure formulations with improved safety and efficacy profiles.
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| Molecular Formula |
C13H20CLNO3
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| Molecular Weight |
273.75600
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| Exact Mass |
273.113
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| CAS # |
56287-61-7
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| Related CAS # |
46817-91-8 (vilozine free base); 35604-67-2 (vilozine HCl salt)
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| PubChem CID |
12226599
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
2.583
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
18
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| Complexity |
213
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CCOC1=CC=CC=C1OCC2CNCCO2.Cl
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| InChi Key |
HJOCKFVCMLCPTP-MERQFXBCSA-N
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| InChi Code |
InChI=1S/C13H19NO3.ClH/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11;/h3-6,11,14H,2,7-10H2,1H3;1H/t11-;/m0./s1
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| Chemical Name |
(2S)-2-[(2-ethoxyphenoxy)methyl]morpholine;hydrochloride
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 3.6528 mL | 18.2642 mL | 36.5283 mL | |
| 5 mM | 0.7306 mL | 3.6528 mL | 7.3057 mL | |
| 10 mM | 0.3653 mL | 1.8264 mL | 3.6528 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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