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| 25mg |
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| Targets |
The primary molecular target of (R)-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 from the synaptic cleft into the presynaptic neuron, thereby increasing the concentration of norepinephrine available for binding to postsynaptic receptors. This mechanism is thought to underlie its antidepressant effects. The R-isomer has been reported to be a less active enantiomer compared to the racemic mixture or the S-isomer, suggesting that the stereochemistry of the molecule significantly influences its binding affinity and functional activity at the norepinephrine transporter. Additionally, viloxazine and its isomers are multimodal serotonergic agents, indicating they may also interact with serotonin receptors or transporters, though the primary mechanism is norepinephrine reuptake inhibition.
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| ln Vitro |
In vitro activity of (R)-Viloxazine Hydrochloride is primarily assessed through its ability to inhibit norepinephrine reuptake. In cell-based assays using cells expressing the human norepinephrine transporter, the compound inhibits the uptake of [³H]norepinephrine with an IC50 value that is expected to be in the nanomolar to low micromolar range. The R-isomer has been reported to be a less active enantiomer, so its IC50 for norepinephrine reuptake inhibition is likely higher (less potent) than that of the racemic mixture or the S-isomer. The compound may also exhibit activity at serotonin and dopamine transporters, though its selectivity for the norepinephrine transporter is a key feature. In receptor binding assays, (R)-Viloxazine Hydrochloride may bind to various serotonin receptors (5-HT receptors) and adrenergic receptors, contributing to its multimodal serotonergic profile. Specific binding affinities (Ki values) for these targets would need to be determined experimentally.
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| ln Vivo |
In vivo activity of (R)-Viloxazine Hydrochloride has not been as extensively studied as the racemic viloxazine. The racemic viloxazine (marketed as Qelbree, Vivalan, Emovit) has been used as an antidepressant and received FDA approval in 2021 for the treatment of attention deficit hyperactivity disorder (ADHD). However, the individual enantiomers have not been developed as separate therapeutic agents. In animal models of depression (e.g., forced swim test, tail suspension test in mice or rats), the R-isomer would be expected to show antidepressant-like effects through norepinephrine reuptake inhibition, though with lower potency than the racemic mixture. The compound may also show effects in models of ADHD, given the clinical use of racemic viloxazine. Dosing in animal studies would typically be in the range of 1-20 mg/kg administered orally or intraperitoneally. The R-isomer's stereochemistry may affect its distribution, metabolism, and elimination compared to the S-isomer.
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| Enzyme Assay |
For in vitro norepinephrine reuptake inhibition assays with compounds like (R)-Viloxazine Hydrochloride, the following protocol is used: HEK293 cells stably expressing the human norepinephrine transporter (hNET) are cultured in DMEM with 10% FBS and antibiotics at 37°C in 5% CO₂. Cells are seeded in 24-well plates at 200,000 cells per well and grown for 24-48 hours. The assay buffer is prepared as Krebs-Ringer HEPES buffer (KRH: 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 diluted in assay buffer to final concentrations ranging from 0.1 nM to 100 μM. Cells are pre-incubated with the compound for 10 minutes at 25°C, followed by addition of [³H]norepinephrine (50 nM) and incubation for 10 minutes. The uptake is terminated by washing the cells three times with ice-cold assay buffer. Cells are lysed with 1% SDS and the radioactivity is measured by liquid scintillation counting. Nonspecific uptake is determined in the presence of 10 μM desipramine. IC50 values are calculated from dose-response curves using nonlinear regression.
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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 primary cortical neurons are cultured in appropriate media at 37°C in 5% CO₂. Cells are seeded in 96-well plates at 10,000-20,000 cells per well and allowed to adhere 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. For assessment of neurotransmitter levels, cells are treated with the compound and the extracellular concentration of norepinephrine, dopamine, and serotonin is measured by HPLC-ECD or LC-MS/MS. For receptor binding studies, membrane preparations from cells expressing specific receptors (e.g., 5-HT receptors) are incubated with radiolabeled ligands and varying concentrations of the test compound. The binding reaction is terminated by filtration, and the radioactivity retained on the filters is measured. Ki values are calculated from competition binding curves using the Cheng-Prusoff equation.
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| Animal Protocol |
For in vivo animal studies with viloxazine isomers, the following general protocol is used: male or female C57BL/6 mice (6-8 weeks old, 20-25 g) or Sprague-Dawley rats (6-8 weeks old, 180-220 g) are used. The test compound is formulated in saline or 0.5% methylcellulose and administered orally or intraperitoneally at doses of 1, 3, 10, and 30 mg/kg. For the forced swim test, mice are placed in a cylinder filled with water (25°C, 15 cm depth) for 6 minutes, and the duration of immobility is recorded during the last 4 minutes. For the tail suspension test, mice are suspended by the tail for 6 minutes, and the duration of immobility is recorded. For the open field test, mice are placed in an open field arena and locomotor activity is measured for 30 minutes to assess any stimulant or sedative effects. For ADHD models, the spontaneous hypertensive rat (SHR) model or the 5-choice serial reaction time task can be used. Blood and brain tissue samples can be collected for pharmacokinetic and pharmacodynamic analysis.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of (R)-Viloxazine Hydrochloride are expected to be similar to those of racemic viloxazine but may differ due to stereoselective metabolism. Viloxazine is known to be well-absorbed after oral administration with a bioavailability of approximately 80-90% in humans. It undergoes extensive hepatic metabolism, primarily by cytochrome P450 enzymes (CYP2D6 and CYP3A4) and glucuronidation. The elimination half-life is approximately 2-5 hours in humans. The R-isomer may be metabolized at different rates compared to the S-isomer due to stereoselective recognition by metabolic enzymes. Plasma protein binding is moderate (approximately 50-60%). The compound is distributed throughout the body, including the central nervous system due to its ability to cross the blood-brain barrier. The stereochemistry of the compound may also affect its volume of distribution and clearance. Comprehensive PK studies comparing the R- and S-isomers would be needed to fully characterize the stereoselective pharmacokinetics of this compound.
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| Toxicity/Toxicokinetics |
The toxicity profile of (R)-Viloxazine Hydrochloride is not separately characterized from that of racemic viloxazine. Racemic viloxazine has been used clinically as an antidepressant and for ADHD treatment, and its safety profile is well-established. Common side effects include nausea, headache, drowsiness, dry mouth, and insomnia. More serious adverse effects are rare but may include cardiovascular effects (hypertension, tachycardia) and psychiatric effects (agitation, anxiety). The R-isomer, being a less active enantiomer, may have a different toxicity profile, potentially with reduced side effects or altered safety margins compared to the racemic mixture or the S-isomer. However, comprehensive toxicological studies on the individual enantiomers have not been published. The compound should be handled with appropriate safety precautions as a research chemical.
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| Additional Infomation |
(R)-Viloxazine Hydrochloride (CAS# 56287-63-9) is the R-isomer of viloxazine, a selective norepinephrine reuptake inhibitor (NRI) used as an antidepressant. It is a less active R-isomer and is used in chiral selectivity studies. The compound is also a multimodal serotonergic agent and has a molecular formula of C13H20ClNO3. Its unique ingredient identifier is 2S787U6BNE. Future research could explore the stereoselective pharmacology of viloxazine enantiomers, investigating differences in target binding, metabolic stability, and therapeutic efficacy, which could lead to the development of enantiomerically pure drugs with improved safety and efficacy profiles.
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| Molecular Formula |
C13H20CLNO3
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| Molecular Weight |
273.75
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| Exact Mass |
273.113
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| CAS # |
56287-63-9
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| Related CAS # |
Viloxazine hydrochloride;35604-67-2;(S)-Viloxazine-d5 hydrochloride;1246816-39-6;(rac)-Viloxazine-d5 hydrochloride;1276483-10-3
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| PubChem CID |
12226597
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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-RFVHGSKJSA-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-;/m1./s1
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| Chemical Name |
(2R)-2-[(2-ethoxyphenoxy)methyl]morpholinehydrochloride
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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 | 3.6530 mL | 18.2648 mL | 36.5297 mL | |
| 5 mM | 0.7306 mL | 3.6530 mL | 7.3059 mL | |
| 10 mM | 0.3653 mL | 1.8265 mL | 3.6530 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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