| Size | Price | Stock | Qty |
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| Other Sizes |
Purity: ≥98%
| Targets |
- γ-Aminobutyric acid type A (GABAA) receptor (modulating steroid antagonist, specifically targeting the neurosteroid binding site on GABAA receptors); no IC₅₀, Ki, or EC₅₀ values specified [2]
Sepranolone targets the GABA-A receptor, the primary inhibitory neurotransmitter receptor in the central nervous system. It acts as an antagonist at the GABA-A receptor. Unlike allopregnanolone, which is a positive allosteric modulator of GABA-A receptors, sepranolone has opposing effects. By antagonizing GABA-A receptors, sepranolone modulates inhibitory neurotransmission. It is regulated as a Schedule IV compound in the United States. |
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| ln Vitro |
Allopregnanolone (allo) is a physiological regulator of neuronal activity that treats multiple neurological disorders. Allo penetrates the blood-brain barrier with very high efficiency, implying that allo can treat CNS-related diseases, including glioblastoma (GBM), which always recurs after standard therapy. Hence, this study aimed to determine whether allo has a therapeutic effect on GBM. We found that allo enhanced temozolomide (TMZ)-suppressed cell survival and proliferation of TMZ-resistant cells. In particular, allo enhanced TMZ-inhibited cell migration and TMZ-induced apoptosis. Additionally, allo strongly induced DNA damage characterized by γH2Ax. Furthermore, quantitative proteomic analysis, iTRAQ, showed that allo significantly decreased the levels of DPYSL3, S100A11, and S100A4, reflecting the poor prognosis of patients with GBM confirmed by differential gene expression and survival analysis. Moreover, single-cell RNA-Seq revealed that S100A11, expressed in malignant cells, oligodendrocytes, and macrophages, was significantly associated with immune cell infiltration. Furthermore, overexpression of DPYSL3 or S100A11 prevented allo-induced cell death. In conclusion, allo suppresses GBM cell survival by decreasing DPYSL3/S100A11 expression and inducing DNA damage.[1]
In vitro studies using electrophysiological recordings have demonstrated that sepranolone functions as a silent antagonist of GABAA receptors. While the 3α-hydroxy epimer allopregnanolone is a potent positive modulator, sepranolone (3β-OH-5α-pregnan-20-one) has no direct agonistic effects on chloride currents. Instead, it competitively inhibits the potentiation of the GABA response induced by allopregnanolone. Mechanistic studies have shown that the antagonistic effect of sepranolone is present across most GABAA receptor subtypes investigated, effectively counteracting the inhibitory tone enhancement caused by elevated allopregnanolone levels . In vitro, sepranolone acts as a GABA-A receptor antagonist. It binds to GABA-A receptors and inhibits the effects of positive modulators such as allopregnanolone. Its antagonistic activity at GABA-A receptors has been demonstrated in various in vitro assays. However, specific IC50 or Ki values are not extensively detailed in the available literature. |
| ln Vivo |
- Sepranolone (UC1010) was evaluated for the treatment of premenstrual dysphoric disorder (PMDD) in a randomized, double-blind, placebo-controlled clinical trial involving 86 women (18–45 years old) with moderate-to-severe PMDD. Participants were randomized to receive either Sepranolone (UC1010) (10 mg, intramuscular injection) or placebo, administered once daily during the luteal phase (7–10 days before expected menstruation) for two consecutive menstrual cycles. The primary efficacy endpoint was the change in the Daily Record of Severity of Problems (DRSP) total score from baseline to the treatment phase. Compared to placebo, Sepranolone (UC1010) significantly reduced the DRSP total score by a mean of 12.3 points (vs. 5.8 points in placebo, p=0.02). Secondary endpoints, including reductions in DRSP emotional subscale scores (irritability, sadness, anxiety) and functional impairment, were also significantly improved in the Sepranolone (UC1010) group compared to placebo. The therapeutic effect was consistent across both treatment cycles [2]
In animal models, sepranolone has been shown to effectively block the behavioral and physiological effects of allopregnanolone. Specifically, it inhibits allopregnanolone-induced anesthesia, sedation, and memory disturbances in rats . In humans, sepranolone administration has been shown to counteract allopregnanolone-induced effects such as reduced saccadic eye velocity, a pharmacodynamic marker of GABAA receptor sensitivity . In clinical trials for PMDD, subcutaneous sepranolone (10 mg or 16 mg) administered every 48 hours during the luteal phase significantly reduced negative mood symptoms. In a Phase II study, sepranolone reduced Total DRSP (Daily Record of Severity of Problems) scores by 75% compared to 47% with placebo in the pure PMDD subgroup (p=0.006) . For Tourette syndrome, a Phase 2a trial reported that sepranolone reduced tic severity (measured by YGTSS) by 28% (p=0.051) and improved quality of life compared to standard care alone, with a favorable safety profile . In vivo, sepranolone is being investigated for the treatment of premenstrual dysphoric disorder (PMDD) and other neuropsychiatric conditions. It is an endogenous neurosteroid that modulates GABA-A receptor function. Its in vivo effects are related to its antagonism of GABA-A receptors, which can influence mood, anxiety, and other neuropsychiatric functions. However, specific details of in vivo efficacy studies are not extensively detailed in the available literature. |
| Enzyme Assay |
The specific binding and antagonistic activity of sepranolone at the GABAA receptor are typically characterized using radioligand binding assays and electrophysiological techniques on isolated receptors. In standard radioligand binding protocols, the affinity of sepranolone for the GABAA receptor complex is assessed indirectly by its ability to displace or inhibit the binding of allopregnanolone. However, as a GAMSA that acts at a specific site distinct from the GABA and benzodiazepine binding sites, sepranolone does not typically displace classical ligands like [³H]flunitrazepam or [³H]muscimol on its own. Instead, its binding is confirmed by its functional antagonism of allopregnanolone-mediated enhancement of [³H]EBOB binding or via photolabeling studies using diazirine-containing neurosteroid probes that map the binding interface (e.g., α1 and β3 subunits) .
The in vitro receptor binding assay for sepranolone typically involves radioligand displacement studies using membrane preparations from cells expressing GABA-A receptors. The compound's affinity is determined by measuring its ability to displace a specific radiolabeled ligand from the receptor. Its functional activity as an antagonist is assessed using electrophysiological or other functional assays. |
| Cell Assay |
The functional antagonism of sepranolone is most accurately measured using whole-cell patch-clamp electrophysiology on neurons or transfected cells expressing GABAA receptors (e.g., HEK293 cells or cultured hippocampal neurons). In a typical experiment, cells are voltage-clamped, and a submaximal concentration of GABA is applied to evoke a baseline chloride current (IGABA). Co-application of allopregnanolone significantly potentiates this current. Subsequently, the addition of sepranolone is tested for its ability to reverse this potentiation. These studies confirm that sepranolone acts as a competitive antagonist, shifting the concentration-response curve of allopregnanolone to the right without affecting the response to GABA alone .
In vitro cellular assays for sepranolone assess its functional antagonism at GABA-A receptors. Cells expressing GABA-A receptors are treated with a positive modulator such as allopregnanolone, and the compound's ability to inhibit the modulatory effect is measured. These assays demonstrate the compound's functional antagonism at GABA-A receptors in a relevant cellular context. |
| Animal Protocol |
Design of the study and study participants [3]
This study was a parallel double-blind, randomized controlled trial design. The primary objective was to evaluate the effect and secondary objective to evaluate safety and tolerability of repeated subcutaneous administration of sepranolone. Women with DSM-5 confirmed PMDD from 12 European medical centers were recruited to participate in a randomized double-blind, placebo-control study to test the effectiveness, safety, and tolerability of two doses of subcutaneously administered sepranolone (10 mg/dose or 16 mg/dose) in the treatment of PMDD symptoms. Participants self-administered the study medication at home every second day during the luteal phase of 3 menstrual cycles, starting 14 days prior to the next estimated onset of menstruation, for a maximum of 7 doses per cycle (Fig. 1). This treatment regimen aimed to provide an isoallopregnanolone plasma level that was 2–3 times higher than the endogenous luteal phase allopregnanolone levels in those receiving active drug (Bixo et al., 2017). Test products, dose and mode of administration [3] Sepranolone (Asarina Pharma AB, Lot: 18900023), is an investigational product for subcutaneous use, provided prefilled (0.4 mL) in single-use syringes suspended in an oily vehicle. In the present study individuals were randomized to receive sepranolone 10 mg/dose, sepranolone 16 mg/dose or placebo, given every 48 h starting 14 days prior to the next estimated menstruation and stopping with the onset of menstruation. Drug administration continued in this manner for three menstrual cycles. Participants were limited to 7 doses per cycle. The study medication was administered as subcutaneous injections to avoid the extensive first pass hepatic metabolism known to occur with the isoallopregnanolone molecule. The placebo used in this study was diluted Intralipid® which is an aqueous solution with a similar appearance as the active study medication, prefilled in the same device as the active drug. Participants were trained to self-administer the study drug. In vivo animal studies for sepranolone are conducted to assess its effects on neuropsychiatric functions. Animal models of anxiety, depression, and premenstrual dysphoric disorder are used to evaluate the compound's efficacy. However, specific details of these studies are not extensively detailed in the available literature. The compound is being investigated in clinical trials for PMDD. |
| ADME/Pharmacokinetics |
Plasma concentrations of allogeneic and isopregnantlanolone at baseline and during treatment cycles are shown in Appendix (Figure A4). At baseline and in each group receiving 10 mg or 16 mg secranolone, allogeneiclanolone concentrations were substantially the same. A complete pharmacokinetic analysis of isopregnantlanolone has not been performed. The isopregnantlanolone concentration in the 16 mg treatment group was slightly higher than that in the 10 mg group, and its variability was greater than that in the low-dose group. The results are consistent with previous studies and confirm that repeated administration of 10 mg and 16 mg results in mean plasma concentrations of isopregnantlanolone between 2 and 10 nmol/L. [3] Neuroendocrinology. Nov 2021:133:105426.
Specific pharmacokinetic data for sepranolone are not extensively detailed in the available literature. As an endogenous neurosteroid, its pharmacokinetic properties are related to its biosynthesis and metabolism. It is a metabolite of progesterone. Its pharmacokinetic profile would be important for its development as a therapeutic agent, but specific data are not provided. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation Due to the low levels of brizanolone in breast milk and its low oral bioavailability, brizanolone is not expected to have any adverse effects on breastfed infants. If the mother requires brizanolone, breastfeeding does not need to be discontinued. Because excessive sedation or sudden loss of consciousness may occur during brizanolone infusion, it is recommended that patients arrange for a separate caregiver for any children present during the infusion. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found. ◉ Effects on Lactation and Breast Milk According to the manufacturer, a study of 12 healthy women undergoing 60-hour brizanolone infusion showed no reported effects on milk production. In a clinical trial for premenstrual anxiety disorder (PMDD), ceprone (UC1010) (10 mg, intramuscular injection) was well tolerated. The most common adverse events (AEs) were mild to moderate injection site reactions (pain, redness, swelling), occurring in 18% of the bispronone (UC1010) group and 12% of the placebo group. No serious adverse events, discontinuation due to adverse events, or clinically significant changes in vital signs, laboratory parameters (liver and kidney function, hematology) or electrocardiogram were observed. [2] Safety results, n = 202 [3] 21 women withdrew their informed consent during treatment, including 9 in the placebo group, 8 in the 16 mg group, and 4 in the 10 mg group. A total of 14 subjects withdrew from the study due to treatment-related adverse events (TEAEs): 3 in the placebo group (4.5%), 5 in the bispronone 10 mg group (7.4%), and 6 in the bispronone 16 mg group (8.9%). More administration site-related adverse events were observed in the bispronone group compared to the placebo group. The most common adverse event was injection site pain, which occurred in 8 out of 68 subjects (11.8%) in the 16 mg bispronone group, occurring in 59 injections (5.8% of all injections). The incidence of injection site pain was 3% in the 10 mg group and 4% in the placebo group. No clinically significant abnormalities related to vital signs, physical examination, electrocardiogram (QTc), or other safety observations were observed in this study. Bispronone treatment had no effect on menstrual cycle length, ovulation frequency, or levels of any luteal phase hormones (progesterone, follicle-stimulating hormone, and luteinizing hormone, data not shown). There were no deaths during the study. Two subjects experienced serious adverse events, both unrelated to treatment: one subject in the 16 mg bispronone group was diagnosed with breast cancer, and another subject in the placebo group was diagnosed with a benign gastrointestinal stromal tumor. Specific toxicity data for sepranolone are not extensively detailed in the available literature. As an endogenous compound, it is likely to have a favorable safety profile. However, its effects on GABA-A receptor function could potentially cause neuropsychiatric side effects. Its safety has been evaluated in clinical trials for PMDD. The compound is intended for research use only. |
| References |
[1]. Allopregnanolone suppresses glioblastoma survival through decreasing DPYSL3 and S100A11 expression. J Steroid Biochem Mol Biol. 2022 May;219:106067. https://pubmed.ncbi.nlm.nih.gov/35114375/
[2]. Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial. Psychoneuroendocrinology. 2017 Jun;80:46-55. https://pubmed.ncbi.nlm.nih.gov/28319848/ [3]. A randomized, double-blind study on efficacy and safety of sepranolone in premenstrual dysphoric disorder. Psychoneuroendocrinology. 2021 Nov:133:105426.https://pubmed.ncbi.nlm.nih.gov/34597899/ |
| Additional Infomation |
Sepranolone (UC1010) is a GABAA receptor-modulating steroid antagonist that works by blocking the binding of neurosteroids (such as allopregnanolone) to neurosteroid binding sites on GABAA receptors. It is speculated that this mechanism can normalize GABAA receptor function, which is dysregulated in patients with premenstrual anxiety disorder (PMDD) due to elevated neurosteroid levels during the luteal phase [2]. PMDD is a mood disorder characterized by severe mood (irritability, depression, anxiety) and somatic symptoms that occur during the luteal phase of the menstrual cycle and are relieved with the onset of menstruation. Sepranodone (UC1010) targets the neurosteroid-GABAA receptor pathway, a key biological mechanism associated with the pathophysiology of premenstrual anxiety disorder (PMDD) [2] - No information is mentioned related to sepranodone (UC1010) (primarily focusing on the role of allogeneic ketone in inhibiting glioblastoma survival by reducing DPYSL3 and S100A11 expression) [1] 3β-hydroxy-5α-pregnane-20-one is a 3-hydroxy-5α-pregnane-20-one. Sepranodone has been investigated for the treatment of premenstrual anxiety disorder. It is a pregnane found in the urine of pregnant women and sows. It has anesthetic, hypnotic, and sedative effects. Pharmaceutical indications Treatment of postpartum depression
Sepranolone (Isopregnanolone) is an endogenous neurosteroid and a natural 3β-epimer of allopregnanolone. It acts as a GABA-A receptor antagonist and is being investigated for the treatment of premenstrual dysphoric disorder (PMDD). It is a metabolite of progesterone and is regulated as a Schedule IV compound in the United States. It is not approved for clinical use and is intended for research purposes only. |
| Molecular Formula |
C21H34O2
|
|---|---|
| Molecular Weight |
318.49346
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| Exact Mass |
318.256
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| Elemental Analysis |
C, 79.19; H, 10.76; O, 10.05
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| CAS # |
516-55-2
|
| Related CAS # |
516-55-2;4406-35-3 (racemic mixture);
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| PubChem CID |
92787
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.053g/cm3
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| Boiling Point |
431.2ºC at 760mmHg
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| Melting Point |
200℃
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| Flash Point |
183.9ºC
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| Index of Refraction |
1.524
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| LogP |
4.595
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
2
|
| Rotatable Bond Count |
1
|
| Heavy Atom Count |
23
|
| Complexity |
500
|
| Defined Atom Stereocenter Count |
8
|
| SMILES |
CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CC[C@@H]4[C@@]3(CC[C@@H](C4)O)C)C
|
| InChi Key |
AURFZBICLPNKBZ-FZCSVUEKSA-N
|
| InChi Code |
InChI=1S/C21H34O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h14-19,23H,4-12H2,1-3H3/t14-,15-,16-,17+,18-,19-,20-,21+/m0/s1
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| Chemical Name |
1-[(3S,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethanone
|
| Synonyms |
UC-1010; U0949; NSC97078; UC 1010; U 0949; NSC97078; UC1010; U-0949; NSC 97078; Allopregnanolone; NSC-97078; Isopregnanolone; Sepranolone;
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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: >10 mM
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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 | 3.1398 mL | 15.6991 mL | 31.3982 mL | |
| 5 mM | 0.6280 mL | 3.1398 mL | 6.2796 mL | |
| 10 mM | 0.3140 mL | 1.5699 mL | 3.1398 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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