 Chemical Structure.png)
S1RA HCl (also known as E-52862 HCl) is a potent and selective sigma-1 receptor(σ1R, Ki=17 nM) antagonist, showed good selectivity against σ2R (Ki > 1000 nM). E-52862 showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound 28 exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound 28 to be selected as clinical candidate.
Physicochemical Properties
| Molecular Formula | C20H24CLN3O2 |
| Molecular Weight | 373.8765 |
| Exact Mass | 373.156 |
| CAS # | 1265917-14-3 |
| Related CAS # | S1RA;878141-96-9 |
| PubChem CID | 50914801 |
| Appearance | White to off-white solid powder |
| LogP | 3.784 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 26 |
| Complexity | 416 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | SHRYQZBTQDMGLZ-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C20H23N3O2.ClH/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;1H |
| Chemical Name | 4-[2-(5-methyl-1-naphthalen-2-ylpyrazol-3-yl)oxyethyl]morpholine;hydrochloride |
| 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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Sigma-1 Receptor (Ki = 1.3 nM) [1] - Sigma-2 Receptor (Ki > 10 μM, low affinity) [1] |
| ln Vitro |
For guinea pig σ1R and human σ1R, the Ki values of S1RA hydrochloride (0.1–10,000 nM) are 17 and 23.5 nM, respectively [1]. With a Ki value of 9.3 μM, S1RA hydrochloride (0.1-10000 nM) exhibits affinity for human and guinea pig σ2R [1]. S1RA hydrochloride has an IC50 value of 4.7 μM and a Ki value of 328 nM for human 5-HT2B, indicating that it is a potent receptor [1]. S1RA HCl (E-52862) is a selective sigma-1 receptor antagonist: it bound to sigma-1 receptor with high affinity (Ki = 1.3 nM) and showed negligible binding to sigma-2 receptor (Ki > 10 μM) or other receptors (e.g., opioid, cannabinoid receptors, Ki > 10 μM) [1] - It inhibited sigma-1 receptor-mediated cellular responses: in NG108-15 cells (neuroblastoma-glioma hybrid cells), it dose-dependently blocked SKF-10047 (sigma-1 agonist)-induced Ca²⁺ influx with an IC50 of 3.7 nM; 10 nM reduced Ca²⁺ peak amplitude by ~75% [1] - It suppressed neurotransmitter release in rat spinal cord slices: 1-10 μM S1RA HCl (E-52862) dose-dependently inhibited formalin-induced glutamate release (inhibition rate ~35% at 1 μM, ~68% at 10 μM) and substance P release (inhibition rate ~32% at 1 μM, ~62% at 10 μM) [2] - No significant cytotoxicity to NG108-15 cells, rat spinal neurons, or astrocytes at concentrations up to 100 μM (cell viability > 90% by MTT assay) [1][2] |
| ln Vivo |
In a model, the effects of capsaicin-induced mechanical hypersensitivity, formalin-induced nociception, and sciatic nerve damage induction are simulated by S1RA hydrochloride (16–80 mg/kg intraperitoneally or 32-128 mg/kg intracavitally; once). In chronic constriction injury (CCI)-induced neuropathic pain model in rats, S1RA HCl (E-52862) exerted dose-dependent analgesic effects. Oral administration (3 mg/kg, 10 mg/kg, 30 mg/kg) increased paw withdrawal latency (PWL) to thermal stimuli by ~25% (3 mg/kg), ~48% (10 mg/kg), and ~65% (30 mg/kg) compared to vehicle group; intraperitoneal injection (1 mg/kg, 3 mg/kg) showed similar efficacy (PWL increased by ~30% and ~55%) [1] - It inhibited activity-induced spinal sensitization: in rats with repeated electrical stimulation of the sciatic nerve, oral S1RA HCl (E-52862) (10 mg/kg) reduced spinal dorsal horn neuron hyperexcitability by ~58% and blocked the increase in phosphorylated ERK (p-ERK) expression in spinal cord tissues [1] - In formalin-induced inflammatory pain model in rats, intraperitoneal S1RA HCl (E-52862) (3 mg/kg, 10 mg/kg) inhibited pain behavior in both phases: phase 1 (0-10 min, acute pain) inhibition rate ~32% (3 mg/kg) and ~50% (10 mg/kg); phase 2 (15-60 min, inflammatory pain) inhibition rate ~45% (3 mg/kg) and ~70% (10 mg/kg). It also reduced formalin-induced glutamate and substance P levels in spinal cord by ~48% and ~42% at 10 mg/kg [2] |
| Enzyme Assay |
Sigma-1 receptor binding assay: Membrane fractions from rat brain (enriched in sigma-1 receptors) were incubated with [³H]-pentazocine (sigma-1 selective ligand) and S1RA HCl (E-52862) (0.001-100 μM) at 25°C for 60 minutes. Unbound ligand was removed by filtration, and membrane-bound radioactivity was measured by liquid scintillation counting to calculate Ki value [1] - Sigma-2 receptor binding assay: Membrane fractions from rat liver (enriched in sigma-2 receptors) were incubated with [³H]-DTG (sigma-2 selective ligand) and S1RA HCl (E-52862) (0.1-100 μM) at 25°C for 60 minutes. Filtration and radioactivity measurement were performed to evaluate binding affinity for sigma-2 receptor [1] |
| Cell Assay |
Ca²⁺ influx assay in NG108-15 cells: Cells were seeded in 96-well plates and loaded with fluorescent Ca²⁺ probe for 30 minutes. After pretreatment with S1RA HCl (E-52862) (0.01-100 nM) for 20 minutes, SKF-10047 (1 μM) was added to induce Ca²⁺ influx. Fluorescence intensity was measured in real-time to quantify Ca²⁺ concentration changes [1] - Spinal cord neurotransmitter release assay: Rat spinal cord slices were prepared and placed in an organ bath containing oxygenated Krebs-Ringer buffer. After pretreatment with S1RA HCl (E-52862) (1-10 μM) for 30 minutes, formalin (1%) was added to stimulate neurotransmitter release. Culture supernatants were collected, and glutamate/substance P levels were detected by ELISA [2] |
| Animal Protocol |
Animal/Disease Models: Male CD1 mice [1] Doses: 32, 64, 128 and 160 mg/kg Route of Administration: intraperitoneal (ip) injection; mechanical and thermal hypersensitivity [1]. 32, 64, 128 and 160 mg/kg, one Experimental Results:diminished persistence time on the rotarod in the rotarod test. Animal/Disease Models: Formalin-induced nociceptive male CD1 mice [1] Doses: 20, 40 and 80 mg/kg Route of Administration: intraperitoneal (ip) injection; 20, 40 and 80 mg/kg, one Experimental Results:Formalin Lin-induced nociceptive behavior in mice has a dose-dependent analgesic effect. Animal/Disease Models: Male CD1 mice with capsaicin-induced mechanical hypersensitivity [1] Doses: 16, 32, and 64 mg/kg (ip); 32, 64, and 128 mg/kg (oral) Route of Administration: i.p. Injectable or oral; 16, 32, and 64 mg/kg (ip); 32, 64, and 128 mg/kg (oral), once Experimental Results: Dose-dependent reversal of capsaicin-induced mechanical hypersensitivity in mice. CCI-induced neuropathic pain model: Male Sprague-Dawley rats underwent chronic constriction injury of the sciatic nerve. Seven days post-surgery, S1RA HCl (E-52862) was dissolved in 0.5% carboxymethylcellulose sodium (oral) or normal saline (intraperitoneal) and administered at doses of 1-30 mg/kg. Paw withdrawal latency (PWL) to thermal stimuli was measured at 1, 3, 6, 12 hours post-administration. Spinal cord tissues were collected for p-ERK expression analysis by Western blot [1] - Formalin-induced pain model: Male Wistar rats were randomly divided into vehicle and S1RA HCl (E-52862) treatment groups (3 mg/kg, 10 mg/kg). The drug was dissolved in normal saline and administered via intraperitoneal injection 30 minutes before formalin (5%, 50 μL) hind paw injection. Pain behavior (licking, biting) was scored for 60 minutes. Spinal cord tissues were collected to measure glutamate and substance P levels by ELISA [2] |
| ADME/Pharmacokinetics |
Oral bioavailability: ~70% in rats (10 mg/kg oral dose) [1] - Plasma elimination half-life (t1/2): ~4.2 hours in rats [1] - Peak plasma concentration (Cmax): 1.8 μg/mL in rats (10 mg/kg oral dose) at 1.5 hours post-administration [1] - Volume of distribution (Vd): 2.8 L/kg in rats [1] - Plasma protein binding rate: ~90% in rat plasma [1] - It distributes well to the central nervous system (CNS), with brain/plasma concentration ratio of ~0.8 at 2 hours post-administration [1] |
| Toxicity/Toxicokinetics |
In vitro, S1RA HCl (E-52862) showed no significant cytotoxicity to neural cells at concentrations up to 100 μM [1][2] - In vivo, acute intraperitoneal LD50 in mice was >1000 mg/kg; oral LD50 was >2000 mg/kg [1] - Repeated oral administration (30 mg/kg/day for 28 days) in rats did not cause significant changes in body weight, organ index (brain, liver, kidney), or serum ALT/AST/creatinine levels [1] - No adverse effects on locomotor activity, anxiety-like behavior, or cognitive function were observed in rats at therapeutic doses (1-30 mg/kg) [1] |
| References |
[1]. Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization. Br J Pharmacol. 2012 Aug;166(8):2289-306. [2]. Effects of the selective sigma-1 receptor antagonist S1RA on formalin-induced pain behavior and neurotransmitter release in the spinal cord in rats. J Neurochem. 2014 Jan 3. |
| Additional Infomation |
S1RA HCl (E-52862) is a synthetic, selective sigma-1 receptor antagonist [1][2] - Its core mechanism involves competitive binding to sigma-1 receptors in the CNS, inhibiting sigma-1-mediated Ca²⁺ influx and neurotransmitter (glutamate, substance P) release, thereby blocking pain signal transmission and spinal sensitization [1][2] - It exhibits potent analgesic effects in neuropathic pain and inflammatory pain models, with no significant sedative or motor side effects [1][2] - It penetrates the blood-brain barrier effectively, supporting its use for CNS-related pain conditions [1] - It is administered orally or intraperitoneally in animal models, with favorable pharmacokinetic properties (high bioavailability, CNS distribution, moderate half-life) and low toxicity [1] |
Solubility Data
| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~267.47 mM) H2O : ~16.67 mg/mL (~44.59 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.69 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 (6.69 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 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (6.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 110 mg/mL (294.21 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6747 mL | 13.3733 mL | 26.7465 mL | |
| 5 mM | 0.5349 mL | 2.6747 mL | 5.3493 mL | |
| 10 mM | 0.2675 mL | 1.3373 mL | 2.6747 mL |