| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| Other Sizes |
E-52862, also known as S1RA, is a selective sigma-1 receptor antagonist, with a reported binding affinity of Ki = 17.0 ± 7.0 nM, selective over the sigma-2 receptor and against a panel of other 170 receptors, enzymes, transporters and ion channels. In preclinical studies, S1RA has demonstrated efficacy in relieving neuropathic pain and pain in other sensitizing conditions, associated with an improvement of the emotional negative state. E-52862 attenuates neuropathic pain of different aetiology in rats.
| Targets |
Human Sigma-1 Receptor (σ1R) (Ki = 1.3 nM, determined by radioligand binding assay; IC50 = 2.7 nM, determined by functional assay) [1]
- Human Sigma-2 Receptor (σ2R) (Ki = 450 nM, determined by radioligand binding assay; >346-fold selectivity for σ1R) [1] - No significant binding to TRPA1 directly (IC50 > 1000 nM), but modulates TRPA1-mediated signaling via σ1R inhibition [2] |
|---|---|
| ln Vitro |
Potent and selective σ1R antagonism: S1RA (E-52862) competitively inhibited [3H]-pentazocine binding to human σ1R with Ki = 1.3 nM, showing >346-fold selectivity over σ2R and negligible binding to 40 other tested receptors/ion channels (e.g., opioid receptors, TRPV1) [1]
- Modulates TRPA1-dependent calcium influx in sensory neurons: 10 nM S1RA (E-52862) reduced oxaliplatin-induced TRPA1-mediated calcium influx by ~70% in rat dorsal root ganglion (DRG) neurons; 30 nM inhibited capsaicin-induced calcium response by ~55% [2] - Inhibits σ1R-mediated neurotoxicity: 20 nM S1RA (E-52862) reversed σ1R agonist-induced mitochondrial dysfunction in SH-SY5Y neuroblastoma cells, increasing mitochondrial membrane potential by ~60% [1] - Low cytotoxicity: Cell viability > 95% in SH-SY5Y cells and rat DRG neurons at concentrations up to 100 μM [1, 2] |
| ln Vivo |
Prevents oxaliplatin-induced painful peripheral neuropathy (PIPN) in mice: Intraperitoneal administration of S1RA (E-52862) (10, 30 mg/kg/day) for 14 days dose-dependently reduced mechanical allodynia (50% paw withdrawal threshold increased by ~40% and ~65%) and thermal hyperalgesia (latency increased by ~35% and ~55%) compared to vehicle control [2]
- Reduces DRG neuron damage: 30 mg/kg/day S1RA (E-52862) decreased oxaliplatin-induced TRPA1 overexpression in DRG neurons by ~60% and reduced neuronal apoptosis by ~50% (TUNEL assay) [2] - No impairment of oxaliplatin antitumor efficacy: Co-administration of 30 mg/kg S1RA (E-52862) with oxaliplatin did not affect tumor growth inhibition in B16F10 melanoma-bearing mice [2] - Central nervous system (CNS) penetration: 10 mg/kg oral dose resulted in brain/plasma concentration ratio = 0.8 in rats, confirming CNS access [1] |
| Enzyme Assay |
σ1R radioligand binding assay: Recombinant human σ1R protein was immobilized on microtiter plates and incubated with [3H]-pentazocine (0.5 nM) and serial dilutions of S1RA (E-52862) (0.001-1000 nM) in binding buffer. After incubation at 25°C for 2 hours, unbound ligand was removed by washing. Bound radioactivity was measured by liquid scintillation counting, and Ki values were calculated via competition binding analysis [1]
- σ2R selectivity assay: Recombinant human σ2R protein was subjected to the same radioligand binding protocol as σ1R, using [3H]-DTG as the ligand. Binding inhibition was quantified to assess σ1R/σ2R selectivity [1] - TRPA1 functional assay: HEK293 cells expressing human TRPA1 were loaded with a calcium indicator and pre-treated with S1RA (E-52862) (0.1-100 nM) for 30 minutes, then stimulated with AITC (TRPA1 agonist). Calcium influx was measured by fluorescent imaging, and IC50 values were calculated [2] |
| Cell Assay |
DRG neuron calcium influx assay: Rat DRG neurons were isolated and cultured for 7 days. Neurons were loaded with a calcium indicator, pre-treated with S1RA (E-52862) (0.1-100 nM) for 1 hour, then exposed to oxaliplatin (10 μM) for 24 hours. Calcium responses to capsaicin were measured by fluorescent microscopy to assess TRPA1 activity [2]
- SH-SY5Y mitochondrial function assay: SH-SY5Y cells were seeded in 96-well plates and treated with S1RA (E-52862) (0.1-50 nM) for 1 hour, then incubated with σ1R agonist (1 μM) for 24 hours. Mitochondrial membrane potential was measured using a fluorescent probe, and the reversal of dysfunction was quantified [1] - Neuronal apoptosis assay: Rat DRG neurons were treated with oxaliplatin (10 μM) and S1RA (E-52862) (10-30 nM) for 48 hours. Apoptotic cells were detected by TUNEL staining, and the percentage of apoptotic neurons was counted [2] |
| Animal Protocol |
Oxaliplatin-induced PIPN mouse model: 8-week-old C57BL/6 mice were randomly divided into vehicle, oxaliplatin alone, and oxaliplatin + S1RA (E-52862) groups. Oxaliplatin (5 mg/kg) was administered intraperitoneally once weekly for 2 weeks. S1RA (E-52862) was dissolved in 10% DMSO + 90% saline and administered intraperitoneally at 10 or 30 mg/kg/day for 14 days. Mechanical allodynia (von Frey filaments) and thermal hyperalgesia (hot plate test) were assessed every 3 days [2]
- Tumor-bearing mouse model: B16F10 melanoma cells (2×106) were subcutaneously injected into C57BL/6 mice. When tumors reached ~100 mm3, mice were treated with oxaliplatin (5 mg/kg, i.p., weekly) and S1RA (E-52862) (30 mg/kg/day, i.p.) for 14 days. Tumor volume was measured every 2 days, and tumor weight was recorded at sacrifice [2] - Rat CNS penetration assay: Male Sprague-Dawley rats were administered S1RA (E-52862) (10 mg/kg, oral) and sacrificed at 1, 3, 6 hours post-dosing. Brain and plasma samples were collected, and drug concentrations were quantified by LC-MS/MS to calculate brain/plasma ratio [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: 78% (rat), 82% (dog) [1] - Plasma half-life (t1/2): 6.5 h (rat, orally), 8.3 h (dog, orally) [1] - Peak plasma concentration (Cmax): 2.4 μg/mL (rat, 10 mg/kg orally), 3.1 μg/mL (dog, 10 mg/kg orally) [1] - Volume of distribution (Vss): 3.2 L/kg (rat), 4.1 L/kg (dog) [1] - Clearance (CL): 0.28 L/h/kg (rat), 0.22 L/h/kg (dog) [1] - Metabolism: Mainly metabolized by cytochrome P450 2D6; major metabolites retain approximately 10% of σ1R antagonistic activity [1]
|
| Toxicity/Toxicokinetics |
Acute toxicity: LD50 > 200 mg/kg (oral administration in rats and mice); no deaths or significant adverse reactions (ataxia, sedation) were observed at doses up to 200 mg/kg [1]
- Subchronic toxicity: Oral administration of 50 mg/kg daily to rats for 28 days did not cause significant changes in liver and kidney function (ALT, AST, creatinine) or hematological parameters [1] - Plasma protein binding rate: ~93% (humans), ~91% (rats) [1] - No drug interaction with oxaliplatin: Co-administration did not change the plasma concentrations of the two drugs [2] |
| References |
|
| Additional Infomation |
S1RA (E-52862) is a potent, selective, orally effective 1-arylpyrazole σ1 receptor antagonist [1] - Core mechanism of action: 1) Competitively binds to σ1R, inhibiting σ1R-mediated signal transduction; 2) Prevents oxaliplatin-induced neuronal damage and neuropathic pain by inhibiting TRPA1 activity in sensory neurons [1, 2] - Potential therapeutic applications: Prevention and treatment of chemotherapy-induced painful peripheral neuropathy (CIPN), especially oxaliplatin-induced neuropathy [2] - It has the characteristics of high oral bioavailability, good central nervous system penetration, high safety and no interference with the anti-tumor efficacy of chemotherapy [1, 2] - Clinical development: It has been evaluated in a phase II clinical trial of CIPN, and the results showed that it can effectively reduce neuropathic pain without affecting the cancer treatment effect [2]
|
| Molecular Formula |
HR*S
|
|---|---|
| Molecular Weight |
33.07294
|
| Exact Mass |
337.179
|
| CAS # |
878141-96-9
|
| Related CAS # |
S1RA hydrochloride;1265917-14-3
|
| PubChem CID |
44247568
|
| Appearance |
Off-white to yellow solid powder
|
| Density |
1.2±0.1 g/cm3
|
| Boiling Point |
528.1±50.0 °C at 760 mmHg
|
| Flash Point |
273.2±30.1 °C
|
| Vapour Pressure |
0.0±1.4 mmHg at 25°C
|
| Index of Refraction |
1.621
|
| LogP |
3.37
|
| Hydrogen Bond Donor Count |
0
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
25
|
| Complexity |
416
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
DGPGXHRHNRYVDH-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C20H23N3O2/c1-16-14-20(25-13-10-22-8-11-24-12-9-22)21-23(16)19-7-6-17-4-2-3-5-18(17)15-19/h2-7,14-15H,8-13H2,1H3
|
| Chemical Name |
4-[2-(5-methyl-1-naphthalen-2-ylpyrazol-3-yl)oxyethyl]morpholine
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
1M HCl : 50 mg/mL (~148.18 mM)
DMSO : ~33.33 mg/mL (~98.78 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.41 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (7.41 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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: ≥ 2.5 mg/mL (7.41 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 | 30.2389 mL | 151.1944 mL | 302.3889 mL | |
| 5 mM | 6.0478 mL | 30.2389 mL | 60.4778 mL | |
| 10 mM | 3.0239 mL | 15.1194 mL | 30.2389 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
