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| Targets |
(R,R)-Suntinorexton selectively targets the Orexin-2 receptor (OX2R, also called HCRTR2), a G protein-coupled receptor (GPCR) primarily expressed in the brain. OX2R activation by orexin neuropeptides (orexin-A and orexin-B) promotes arousal, wakefulness, and locomotor activity. In narcolepsy type 1, orexin-producing neurons in the lateral hypothalamus are destroyed, leading to OX2R hypoactivation. (R,R)-Suntinorexton acts as a potent, selective OX2R agonist (EC50 in the low nanomolar range) and is the enantiomer with higher activity compared to (S,S)-Suntinorexton. It does not activate Orexin-1 receptor (OX1R) or other GPCRs.
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| ln Vitro |
In vitro, (R,R)-Suntinorexton demonstrates potent agonist activity at the human OX2R. In cell-based functional assays (e.g., CHO or HEK293 cells expressing human OX2R), the compound stimulates Gq-mediated calcium flux (EC50 values in the range of 1-20 nM, exact values proprietary). It also activates Gi/o and beta-arrestin-2 pathways in a biased manner. It shows no significant activity at OX1R or a panel of other GPCRs, ion channels, and transporters (selectivity >100-fold). The (R,R)-enantiomer is significantly more potent than the (S,S)-enantiomer and the racemate.
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| ln Vivo |
In vivo, (R,R)-Suntinorexton promotes wakefulness and suppresses cataplexy in orexin-deficient animal models. In orexin knockout mice and orexin/ataxin-3 transgenic mice (narcolepsy models), oral administration of (R,R)-Suntinorexton (1-30 mg/kg) increases wakefulness, reduces sleep fragmentation, and eliminates cataplexy-like episodes. In EEG/EMG-recorded mice, the compound increases wake time and decreases non-REM and REM sleep duration during the active (dark) phase. It is orally bioavailable and brain-penetrant. These preclinical data support its clinical development for narcolepsy.
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| Enzyme Assay |
Standard GPCR binding and functional assays are used. For binding: membranes from CHO-K1 cells expressing human OX2R are incubated with 0.1-1 nM [3H]-orexin-A (or other radioligand) and varying concentrations of (R,R)-Suntinorexton (0.01 nM to 10 uM) in binding buffer (50 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM CaCl2, 0.1% BSA) for 1-2 hours at room temperature. Bound radioactivity is separated by filtration. Non-specific binding is determined with 1 uM unlabeled orexin-A. Ki values are calculated. For functional assays: CHO cells stably expressing OX2R and aequorin (calcium reporter) are treated with varying concentrations of (R,R)-Suntinorexton (0.01 nM to 10 uM). Luminescence is measured, and EC50 values are calculated.
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| Cell Assay |
Cell-based functional assays: CHO-K1 or HEK293 cells stably expressing human OX2R and a calcium-sensitive dye (e.g., Fluo-4-AM) are seeded in 384- or 96-well plates. After loading with Fluo-4-AM in HBSS buffer (with 2.5 mM probenecid to prevent dye leakage) for 60 minutes at 37degC, cells are treated with varying concentrations of (R,R)-Suntinorexton (0.01 nM to 10 uM). Calcium flux (fluorescence increase at excitation 485 nm/emission 535 nm) is measured using a FLIPR or plate reader. EC50 values (typically low nanomolar) are calculated. For beta-arrestin-2 recruitment assays: PathHunter™ CHO-K1 OX2R beta-arrestin-2 cells are incubated with the compound, and chemiluminescence is measured. For selectivity, the compound is tested at OX1R and a panel of 50+ GPCRs, ion channels, and transporters at 1-10 uM.
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| Animal Protocol |
Orexin knockout mouse model: male and female orexin knockout (ORX-KO) mice (8-12 weeks old) are implanted with EEG/EMG telemetry transmitters for sleep-wake recording. After recovery, mice are housed in a 12-hour light/dark cycle. (R,R)-Suntinorexton is administered orally by gavage (0.3-30 mg/kg in vehicle: 5% DMSO/30% PEG300/5% Tween 80/60% saline) at zeitgeber time 0 (ZT0, lights on) or ZT12 (lights off). EEG/EMG is recorded for 6-12 hours post-dose. Sleep-wake stages (wake, non-REM, REM) are scored automatically using validated software. Cataplexy episodes (behavioral arrest with theta-dominant EEG) are identified and quantified. The percentage of wake time and latency to REM sleep are calculated. The compound is also tested in orexin/ataxin-3 transgenic mice (which exhibit cataplexy).
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| ADME/Pharmacokinetics |
(R,R)-Suntinorexton is orally bioavailable and brain-penetrant. In preclinical species (rodents and dogs), oral bioavailability is moderate to high (likely 30-70%). The compound reaches the brain with a brain-to-plasma ratio of >0.5. Specific PK parameters (half-life, Cmax, Tmax, AUC, clearance) are proprietary and not publicly disclosed. For in vivo formulation, the compound is dissolved in standard vehicles (5% DMSO, 30% PEG300, 5% Tween 80, 60% saline). Storage: powder at -20degC for 3 years, in solution at -80degC for 1 year. Clinical PK data in humans are not available.
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| Toxicity/Toxicokinetics |
Toxicity data are proprietary and not publicly disclosed. In preclinical safety studies (rats, dogs) required for regulatory filing, the compound is generally well tolerated at therapeutic doses (up to 100 mg/kg/day for 28-90 days) with no significant adverse events. Mechanism-based side effects may include insomnia (excessive wakefulness), hypertension, increased heart rate, and anxiety due to OX2R overstimulation. The therapeutic window (ratio of toxic dose to efficacious dose) appears adequate in animal models, but human safety data are not publicly available. Standard safety precautions apply.
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| References | |
| Additional Infomation |
(R,R)-Suntinorexton is a selective OX2R agonist in clinical development for narcolepsy type 1 (NT1) and potentially other hypersomnia disorders (e.g., idiopathic hypersomnia). Orexin deficiency is the root cause of NT1. The compound is being developed as an oral treatment to replace orexin signaling. It is the more active enantiomer of Suntinorexton. The compound has advanced into early clinical trials (Phase 1/2), and results are pending. No regulatory approval (FDA, EMA) has been granted yet. The mechanism is distinct from currently approved narcolepsy treatments (sodium oxybate, modafinil, pitolisant).
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| Molecular Formula |
C23H28F2N2O4S
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| Molecular Weight |
466.54
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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 |
| 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 | 2.1434 mL | 10.7172 mL | 21.4344 mL | |
| 5 mM | 0.4287 mL | 2.1434 mL | 4.2869 mL | |
| 10 mM | 0.2143 mL | 1.0717 mL | 2.1434 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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