| Size | Price | Stock | Qty |
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| 1mg |
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| Other Sizes |
| Targets |
The primary target of Alixorexton enantiomer is the orexin-2 receptor (OX2R). Orexin receptors are G-protein coupled receptors (GPCRs) that play a critical role in regulating wakefulness, arousal, and appetite. The orexin neuropeptides (orexin-A and orexin-B) are produced exclusively by neurons in the lateral hypothalamus. Orexin-B has a high affinity for OX2R, which is predominantly expressed in the brain regions involved in arousal, including the tuberomammillary nucleus and the raphe nuclei. By acting as an agonist at OX2R, Alixorepton promotes wakefulness, stabilizes the sleep-wake cycle, and prevents the sleep attacks and cataplexy characteristic of narcolepsy. The selectivity of the parent compound for OX2R over OX1R is designed to maximize efficacy while minimizing off-target cardiovascular effects.
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| ln Vitro |
The in vitro activity of Alixorexton enantiomer is characterized by its ability to activate the orexin-2 receptor (OX2R). The potency is typically measured in cell-based functional assays (e.g., calcium mobilization or cAMP inhibition). Cells (e.g., CHO or HEK293 cells) are engineered to stably express the human OX2R. Treatment with the compound leads to a dose-dependent increase in intracellular calcium flux (measured with Fluo-4 dye) or a decrease in cAMP levels (via activation of Gi signaling). The EC50 value for the active enantiomer is expected to be in the low nanomolar range, confirming potent agonism. The enantiomer can be compared against the racemate to determine the stereospecificity of the receptor interaction. The opposite enantiomer would be expected to have a significantly higher EC50 or show no response.
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| ln Vivo |
In vivo studies have been conducted with the parent compound, Alixorexton, demonstrating its ability to promote wakefulness in rodent models. In a typical sleep-deprivation model, administration of the compound to mice or rats results in a significant increase in wakefulness time and a reduction in both rapid eye movement (REM) and non-REM sleep, as measured by electroencephalography (EEG) and electromyography (EMG). In a mouse model of narcolepsy (orexin-deficient mice), oral administration of the compound is expected to consolidate wakefulness and prevent cataplexy-like episodes. The active enantiomer is responsible for this pharmacological effect. These studies confirm that the compound can cross the blood-brain barrier (BBB) and engage the OX2R target in the brain. The compound is orally bioavailable and brain-penetrant, which are key attributes for a CNS-active drug candidate.
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| Enzyme Assay |
The receptor binding affinity of the Alixorexton enantiomer for OX2R is measured using a radioligand binding assay. This is a cell-free, membrane-based assay. Membranes prepared from cells expressing the human OX2R (5-20 microg protein) are incubated with a high-affinity radioligand (e.g., [3H]-orexin-B or a selective antagonist radioligand) at a concentration close to its KD (e.g., 0.5-2 nM). Varying concentrations of the unlabeled Alixorexton enantiomer (0.01 nM to 10 microM) are added to compete with the radioligand. The mixture is incubated in binding buffer (e.g., 50 mM Tris-HCl, pH 7.4, 5 mM MgCl2, 0.1% BSA) for 60 minutes at room temperature. Non-specific binding is determined in the presence of a high concentration of a reference OX2R antagonist (e.g., 10 microM). Bound radioligand is separated from free by rapid filtration through GF/B filters presoaked in 0.3% PEI. The radioactivity is counted, and the IC50 is determined. The Ki is calculated using the Cheng-Prusoff equation. The enantiomer is expected to have a Ki in the low nanomolar range.
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| Cell Assay |
The functional activity of the Alixorexton enantiomer is assessed in a cell-based functional assay. HEK293 cells stably expressing the human OX2R and a calcium-sensitive reporter (e.g., aequorin or Galpha16) are used. Cells are seeded in 384-well plates (15,000 cells/well) and loaded with the calcium indicator dye (e.g., Fluo-4 Direct). Alixorexton enantiomer is added at serial dilutions (from 0.01 nM to 10 microM) via an automated dispenser. The change in fluorescence (excitation = 485 nm, emission = 535 nm) is measured in real-time using a fluorescence plate reader (e.g., FLIPR or FlexStation). The peak fluorescence signal is plotted against compound concentration to generate a concentration-response curve, and the EC50 is calculated using a 4-parameter logistic equation. The compound is expected to act as a full agonist, producing a maximum response (Emax) equal to or greater than that of the natural ligand orexin-B. This assay confirms that the enantiomer activates the receptor's downstream signaling pathway.
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| Animal Protocol |
To confirm the wake-promoting effects of Alixorexton in vivo, a standard mouse sleep-wake study is performed. Male C57BL/6J mice (10-12 weeks old) are surgically implanted with electrodes for EEG (electroencephalogram) and EMG (electromyogram) recording. After a 1-2 week recovery period, the mice are placed in recording chambers and acclimated to a 12-hour light/dark cycle (lights on at 7 AM). Alixorexton (or the active enantiomer) is formulated in a vehicle such as 0.5% methylcellulose or a solution of 10% DMSO, 40% PEG300, and 50% water. The compound is administered by oral gavage (10-30 mg/kg) at the beginning of the light cycle (zeitgeber time 0, the period when mice normally sleep). EEG/EMG data is collected continuously for 6-12 hours post-dosing. The sleep-wake stages (wake, NREM, REM) are scored in 10-second epochs. The primary endpoints are the total time spent awake, latency to NREM sleep, and latency to REM sleep. A positive result is a significant increase in total wake time and a prolonged latency to sleep compared to vehicle-treated controls. This protocol directly demonstrates target engagement in the CNS and provides proof-of-concept for the treatment of hypersomnia.
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| ADME/Pharmacokinetics |
Alixorexton (the parent compound) is described as orally active and brain-penetrant. As a small molecule with a molecular weight of 422.54, it is likely to have good oral bioavailability in preclinical species. Its ability to cross the blood-brain barrier (BBB) is critical for its efficacy in sleep disorders. The brain-to-plasma ratio (Kp) in rodents would be measured, likely >0.5, indicating good CNS exposure. The terminal half-life (t1/2) is expected to be in the range of 2-5 hours, supporting once or twice daily dosing. The compound is likely metabolized by hepatic cytochrome P450 enzymes (e.g., CYP3A4). The pharmacokinetics of the active enantiomer would mirror those of the parent compound if the drug is administered as the single enantiomer. The enantiomer may have a different clearance rate than the racemate due to the stereospecificity of metabolizing enzymes. The compound's PK properties are designed to enable daytime dosing to promote alertness without disrupting nighttime sleep architecture.
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| Toxicity/Toxicokinetics |
The toxicity profile of Alixorexton enantiomer is not fully described in the provided search results. However, as an orexin-2 receptor agonist, its toxicity is likely mechanism-based and related to excessive wakefulness. High doses could potentially lead to insomnia, anxiety, jitteriness, or increased sympathetic tone (elevated heart rate and blood pressure). Since it is a brain-penetrant compound, there is a risk of seizure at very high doses. Long-term studies would assess effects on body weight, food intake, and potential for addiction or abuse, as the orexin system is also involved in reward pathways. No specific target organ toxicity (e.g., hepatotoxicity) has been reported for this specific enantiomer in the provided snippets. The parent compound is still in the research phase; therefore, complete toxicology reports are not public. Standard safety pharmacology studies for CNS drugs would be required, including a hERG assay to assess cardiac risk and a functional observation battery (FOB) to assess neurological effects. For now, it is solely a research chemical.
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| References | |
| Additional Infomation |
Alixorexton enantiomer has CAS number 2648350-16-5. It is also known as ALKS 2680 enantiomer. Its molecular formula is C21H30N2O5S, and its molecular weight is 422.54 g/mol. It is a single enantiomer of the research compound Alixorexton . The target, orexin-2 receptor (OX2R), is a GPCR. The orexin system is a central regulator of sleep and wakefulness; deficiency of orexin is the primary cause of narcolepsy type 1. Alixorexton and its enantiomer are classified as “orexin agonists” and are being developed as potential treatments for narcolepsy and idiopathic hypersomnia (a condition characterized by excessive daytime sleepiness despite a normal night‘s sleep). The compound is stored at -20degC in a sealed container, protected from light and moisture. It is intended for research use only.
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| Molecular Formula |
C21H30N2O5S
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|---|---|
| Molecular Weight |
422.54
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| Exact Mass |
422.187543
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| CAS # |
2648350-16-5
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| Related CAS # |
2648347-56-0; Alixorexton
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
29
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| Complexity |
671
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CS(=O)(=O)N[C@@H]1CCCN2[C@@H]1COC3CCC(CC3)C4=CC=CC=C4OCC2=O
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| InChi Key |
IHNJMACFBQEKRJ-LRMJVLKBSA-N
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| InChi Code |
InChI=1S/C21H30N2O5S/c1-29(25,26)22-18-6-4-12-23-19(18)13-27-16-10-8-15(9-11-16)17-5-2-3-7-20(17)28-14-21(23)24/h2-3,5,7,15-16,18-19,22H,4,6,8-14H2,1H3/t15?,16?,18-,19-/m1/s1
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| Chemical Name |
N-[(15R,16S)-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.02,7.011,16]tricosa-2,4,6-trien-15-yl]methanesulfonamide
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| Synonyms |
ALKS2680 enantiomer; ALKS-2680 enantiomer; ALKS 2680 enantiomer;
2648350-16-5; N-((21R,24R,52S,53R)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-53-yl)methanesulfonamide
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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 : ~50 mg/mL (~118.33 mM; with sonication (<60°C))
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (11.83 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 50.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix thoroughly. Then add 50 μL of Tween-80 to the above system and mix thoroughly. Finally, add 450 μL of physiological saline to bring the volume to 1 mL. Preparation of physiological saline: Dissolve 0.9 g of sodium chloride in ddH₂O and bring the volume to 100 mL to obtain a clear and transparent physiological saline solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 5 mg/mL (11.83 mM)(saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 50.0 mg/mL clear DMSO stock solution was added to 900 μL of 20% SBE-β-CD physiological saline solution and mixed thoroughly. 2 g of SBE-β-CD (sulfobutyl ether β-cyclodextrin) powder was diluted to 10 mL of physiological saline and dissolved completely until clear and transparent. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 5 mg/mL (11.83 mM)(saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one)),clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3666 mL | 11.8332 mL | 23.6664 mL | |
| 5 mM | 0.4733 mL | 2.3666 mL | 4.7333 mL | |
| 10 mM | 0.2367 mL | 1.1833 mL | 2.3666 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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