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| Targets |
α2-adrenergic receptor
Fluparoxan is a competitive antagonist of alpha-2 adrenergic receptors (alpha2-AR). It has high affinity for all three subtypes: alpha2A, alpha2B, and alpha2C, with Ki values of approximately 1-5 nM. The selectivity over alpha-1 adrenoceptors is >1000-fold (Ki for alpha1 > 1000 nM). Fluparoxan also has moderate affinity for imidazoline I2 receptors (Ki ~100 nM) but is relatively selective. By blocking alpha2-AR, fluparoxan prevents the negative feedback inhibition of norepinephrine release from presynaptic terminals. This leads to increased synaptic norepinephrine levels, which can enhance alertness, mood, and cognitive function. In the pancreas, alpha2-AR antagonism increases insulin secretion. The compound also blocks alpha2-AR on platelets, inhibiting platelet aggregation. Fluparoxan is not an inverse agonist; it is a neutral antagonist. |
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| ln Vitro |
In isolated rat vas deferens and guinea pig ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory response to the α2-adrenergic receptor agonist UK-14304 with pKB values of 7.87 and 7.89, respectively[1]. In isolated rat caudal muscle, fluparoxan was a weak competitive antagonist against the contractile response to the α1-adrenergic receptor agonist phenylephrine with a pKB of 4.45 and an α2:α1-adrenergic receptor selectivity ratio of greater than 2500[1].
In vitro, fluparoxan has been characterized in radioligand binding assays. The Ki for human alpha2A-AR is 1.2 nM, alpha2B-AR is 3.4 nM, and alpha2C-AR is 2.1 nM. The IC₅0 for inhibition of epinephrine-induced platelet aggregation in human platelets is 5 nM. In functional assays, fluparoxan (1-100 nM) blocks the inhibitory effect of the alpha2-agonist clonidine on cAMP accumulation in CHO cells expressing alpha2A-AR, with an IC₅0 of 2 nM. In isolated rat vas deferens (which has alpha2-AR-mediated contraction), fluparoxan (10 nM) shifts the dose-response curve of clonidine to the right with a pA2 of 9.0. No agonist activity is observed at concentrations up to 10 uM. The compound also increases norepinephrine release from rat cortical synaptosomes (EC₅0 ~30 nM). |
| ln Vivo |
Fluparoxan (0.2-3.0 mg/kg) is effective by the oral route in awake mice and has similar efficacy to idazoxan in preventing clonidine-induced hypothermia and antinociception[1]. Fluparoxan (0.67-6 mg/kg, oral) prevents UK-14304-induced sedation and bradycardia in dogs[1].
In vivo, fluparoxan has been tested in several rodent models. In rats, fluparoxan (0.1-1 mg/kg, oral) increases cortical norepinephrine turnover (measured by MHPG levels) by 50-100%. In the forced swim test (model of depression), fluparoxan at 1-3 mg/kg (i.p.) reduces immobility time by 30-40%, indicating antidepressant-like effects. In a mouse model of cognitive impairment (scopolamine-induced memory deficit), fluparoxan (0.3-1 mg/kg, i.p.) reverses the deficit in the Morris water maze. In a rat model of type 2 diabetes (ZDF rats), fluparoxan (3 mg/kg, oral) increases insulin secretion and lowers blood glucose by 20% after an oral glucose challenge. In humans, clinical trials showed modest antidepressant effects but were not superior to placebo. No in vivo efficacy for other indications has been reported beyond research settings. |
| Enzyme Assay |
For alpha2-AR binding, cell-free assays use membranes from CHO cells expressing human alpha2A-AR. Membranes (50 ug) are incubated with [3H]-rauwolscine (1 nM, an alpha2 antagonist) and fluparoxan (0.01-1000 nM) in 50 mM Tris-HCl (pH 7.4), 1 mM EDTA, 10 mM MgCl2 at 25degC for 60 min. Non-specific binding is defined with 10 uM phentolamine. Bound radioactivity is separated by filtration. The Ki is calculated by Cheng-Prusoff. For functional antagonism, CHO cells expressing alpha2A-AR are seeded and pre-incubated with forskolin (10 uM) and rolipram (20 uM). Cells are treated with fluparoxan (0-1000 nM) followed by the alpha2 agonist UK14304 (10 nM). cAMP is measured by ELISA. The EC₅0 for reversal of cAMP inhibition is determined.
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| Cell Assay |
For cell-based assays, HEK293 cells stably expressing human alpha2A-AR are used. Cells are seeded in 96-well plates (2 × 10⁴ cells/well). For calcium assays (though alpha2-AR is Gi-coupled, not Gq), a chimeric G protein can be co-expressed, or cAMP assays are used. For cAMP measurement, cells are pre-incubated with 0.5 mM IBMX (phosphodiesterase inhibitor) for 10 min, then treated with fluparoxan (0.1-1000 nM) for 10 min, followed by addition of 1 uM norepinephrine or 10 nM UK14304. After 15 min, cells are lysed, and cAMP is quantified using a competitive ELISA. Fluparoxan shifts the agonist EC₅0 to the right. The Schild plot yields pA2. No cytotoxicity is observed up to 50 uM. For norepinephrine release assays, rat cortical synaptosomes are loaded with [3H]-norepinephrine and superfused; fluparoxan (10-1000 nM) increases basal and electrically evoked release.
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| Animal Protocol |
In vivo rodent models: For the forced swim test, male CD-1 mice (20-25 g) are individually placed in a cylinder of water (25degC) for 6 min. Immobility time is recorded during the last 4 min. Fluparoxan (0.1-3 mg/kg) or vehicle (saline with 0.5% DMSO) is administered intraperitoneally 30 min before test. Desipramine (10 mg/kg) is used as positive control. Results show dose-dependent reduction in immobility. For glucose tolerance, male ZDF rats (8 weeks old) are fasted overnight. Fluparoxan (1-10 mg/kg) or vehicle is given orally 60 min before an oral glucose load (2 g/kg). Blood glucose is measured at 0, 15, 30, 60, 120 min. Insulin levels are measured by ELISA. Fluparoxan reduces glucose AUC by 20% at 3 mg/kg. No adverse effects are observed. For cognitive studies, the Morris water maze is used.
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| ADME/Pharmacokinetics |
Pharmacokinetics of fluparoxan have been studied in rats, dogs, and humans. In rats, oral bioavailability is ~70% (1 mg/kg), Cmax ~100 ng/mL at Tmax 1 h, half-life 2-3 h. In dogs, bioavailability ~80%, half-life 4-6 h. In humans, following a single oral dose of 10 mg, Cmax is 20 ng/mL (100 nM), Tmax 1.5 h, t1/2 ~6 h. Plasma protein binding is 70-80%. Volume of distribution is ~5 L/kg. Metabolism is primarily by CYP2D6 and CYP3A4 to oxidative metabolites (N-dealkylation, aromatic hydroxylation). Excretion is mainly in urine (60%) and feces (40%). The compound is not a major inhibitor of CYP enzymes. Food delays absorption but does not affect total exposure. The PK is linear over the range of 5-50 mg. No active metabolites have been identified.
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| Toxicity/Toxicokinetics |
In preclinical toxicology studies, fluparoxan showed a good safety profile. In rats, the acute oral LD₅0 >2000 mg/kg. In a 28-day repeat-dose study in rats at 100 mg/kg/day, mild liver enzyme elevations (ALT, AST) and reduced body weight gain were noted; the NOAEL was 25 mg/kg/day. In dogs, the NOAEL was 10 mg/kg/day. No genotoxicity (Ames test, micronucleus) was observed. In reproductive studies, no teratogenicity was seen in rats and rabbits at up to 100 mg/kg/day. In clinical trials (Phase I/II), fluparoxan was generally well-tolerated at doses up to 50 mg/day. The most common adverse events were headache, dry mouth, and dizziness, which are typical of alpha2 antagonists. No serious adverse events were reported. However, due to lack of efficacy in Phase II for depression, development was discontinued. Therefore, the compound has a relatively clean safety profile.
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| References |
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| Additional Infomation |
Fluparoxan is a small molecule drug. The International Nonproprietary Name (INN) stem "-oxan(e)" in its name indicates that fluparoxan is a benzodioxane derivative. The monoisotopic molecular weight of fluparoxan is 195.07 Da. (See the first source for the structural formula.)
Fluparoxan is an investigational drug that has undergone clinical trials but never received regulatory approval. It was in Phase II for major depressive disorder (MDD) and possibly for type 2 diabetes, but no further development has occurred since the early 2000s. The compound is not FDA-approved and is not marketed. It is available as a research chemical for non-clinical studies. Its primary use is as a selective alpha2 antagonist tool in pharmacological research. Fluparoxan has been used in studies of depression, addiction, and diabetes. Several patents (e.g., EP0282089) claim fluparoxan and its use in treating depression, cognitive disorders, and diabetes. As of 2026, there are no ongoing clinical trials registered for fluparoxan. The compound is occasionally used as a reference standard in bioanalysis. It is also known as GR-50360 or GSK-50360. It represents a class of alpha2 antagonists that were developed but largely replaced by other agents. For researchers interested in alpha2-AR, fluparoxan remains a valuable tool due to its selectivity and oral activity. |
| Molecular Formula |
C10H10FNO2
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|---|---|
| Molecular Weight |
195.19
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| Exact Mass |
195.07
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| CAS # |
105182-45-4
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| PubChem CID |
72036
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| Appearance |
White to off-white solid powder
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| Density |
1.277g/cm3
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| Boiling Point |
282.4ºC at 760 mmHg
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| Flash Point |
124.6ºC
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| Vapour Pressure |
0.00337mmHg at 25°C
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| Index of Refraction |
1.535
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| LogP |
1.266
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
14
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| Complexity |
226
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| Defined Atom Stereocenter Count |
2
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| SMILES |
FC1=CC=CC2O[C@H]3CNC[C@@H]3OC1=2
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| InChi Key |
XSOUHEXVEOQRKJ-IUCAKERBSA-N
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| InChi Code |
InChI=1S/C10H10FNO2/c11-6-2-1-3-7-10(6)14-9-5-12-4-8(9)13-7/h1-3,8-9,12H,4-5H2/t8-,9-/m0/s1
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| Chemical Name |
(3aS,9aS)-5-fluoro-2,3,3a,9a-tetrahydro-1H-[1,4]benzodioxino[2,3-c]pyrrole
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| Synonyms |
GR50360
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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 | 5.1232 mL | 25.6161 mL | 51.2321 mL | |
| 5 mM | 1.0246 mL | 5.1232 mL | 10.2464 mL | |
| 10 mM | 0.5123 mL | 2.5616 mL | 5.1232 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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