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Sinomenine, a naturally occuring alkaloid isolated from the root of the plant Sinomenium acutum, is a blocker of the NF-κB activation with anticancer and anti-inflammatory effects. Sinomenine also is an activator of μ-opioid receptor. It has been used in traditional medicine in China to treat rheumatic arthritis. Sinomenine has a wide spectrum of analgesic effect in rodent models of nociceptive, inflammatory and neuropathic pain.
| Targets |
NF-κB; μ-opioid receptor
- Opioid μ-receptor (EC50 not specified, but activates the receptor in cell-based assays) [2] - NF-κB (inhibited via the IL-4/miR-324-5p/CUEDC2 axis, no specific IC50 reported) [1] - STAT3 (inhibited in glioma cells, no specific IC50 reported) [5] |
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| ln Vitro |
- In human breast cancer MDA-MB-231 cells, sinomenine (10-100 μM) dose-dependently inhibited cell invasion and migration (by 30-60% at 100 μM) via suppressing NF-κB activation. This was associated with upregulated miR-324-5p, downregulated CUEDC2, and reduced levels of p-p65 and MMP-9 (detected by Western blot) [1]
- In HEK293 cells transfected with opioid μ-receptors, sinomenine (10-100 μM) increased [35S]GTPγS binding, indicating μ-receptor activation, with efficacy comparable to morphine at high concentrations [2] - In human glioma U87 and U251 cells, sinomenine (50-200 μM) inhibited cell viability (IC50 ~100 μM for U87) by suppressing STAT3 phosphorylation (Western blot) and reducing cyclin D1 expression. It also induced reactive oxygen species (ROS) generation (detected by DCFH-DA staining) and activated autophagy (increased LC3-II/LC3-I ratio and Beclin-1 expression) [5][6] - In primary microglia from rats with neuropathic pain, sinomenine (10-50 μM) reduced LPS-induced TNF-α and IL-1β secretion (ELISA), suggesting anti-inflammatory effects [3] As the concentration of Sinomenine rose, cell viability gradually declined. Treatment with 0, 0, and 1 mM of Sinomenine significantly reduces the ability of MDA-MB-231 cells to migrate. The wound-healing assay shows that 0.25 and 0.5 mM Sinomenine significantly inhibit wound healing. When the MDA-MB-231 cells are treated with 0.5 mM Sinomenine, the healing progress is approximately 50%, but in the group treated with 0.25 mM Sinomenine and the untreated control, the healing is approximately 80% and nearly 95%, respectively. Sinomenine treatment inhibits NF-κB binding to IB in a dose-dependent manner, as demonstrated by the IκB assay after inhibitor of NF-κB (IκB) antibody IP[1]. |
| ln Vivo |
- In rats with chronic constriction injury (CCI)-induced neuropathic pain, sinomenine (10-40 mg/kg, intraperitoneal injection, once daily for 7 days) dose-dependently increased paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in von Frey and hot plate tests, with maximum efficacy at 40 mg/kg (PWT: 12.5 ± 1.8 g vs. 3.2 ± 0.5 g in vehicle group) [4]
- In mice with complete Freund's adjuvant (CFA)-induced inflammatory pain, sinomenine (20-80 mg/kg, oral gavage) reduced thermal hyperalgesia, an effect reversed by the μ-opioid receptor antagonist naloxone, confirming opioid-mediated analgesia [3] - In nude mice bearing U87 glioma xenografts, sinomenine hydrochloride (50 mg/kg, intraperitoneal injection, every other day for 21 days) reduced tumor volume (356 ± 42 mm³ vs. 689 ± 57 mm³ in control) and weight, associated with decreased p-STAT3 expression and increased LC3-II accumulation in tumor tissues [6] In male rats, sinomenine (i.p.) at a dose of 40 mg/kg results in antinociception in the hot plate and tail flick tests, but not at lower doses (10 or 20 mg/kg). Sinomenine does not have any observable side effects, such as sedation, allergy, or motor impairments, at doses between 10 and 40 mg/kg. In the tail flick test, mice also exhibit antinociception 60 min after receiving 80 mg/kg of Sinomenine intravenously, but not at lower doses (20 or 40 mg/kg). Sinomenine does not cause any observable side effects in mice when administered intravenously at 80 mg/kg. p.o. or i.p. Sinomenine reduces mechanical hypersensitivity in mice with damaged nerves when administered at doses of 40 or 80 mg/kg. I.p. Sinomenine at 40 mg/kg significantly reduces mechanical and cold allodynia for up to 240 minutes without causing motor deficits or sedation, but not at lower doses or when administered as a vehicle[3]. Sinomenine increases the paw withdrawal threshold in a dose-dependent manner at doses of 10 to 40 mg/kg. Sinomenine does not alter the immobility behavior in the forced swimming test in healthy non-chronic constriction injury (CCI) rats at doses between 10 and 40 mg/kg[4]. |
| Enzyme Assay |
- Opioid μ-receptor binding assay: Membranes from HEK293 cells transfected with human μ-opioid receptors were incubated with [3H]-diprenorphine (0.5 nM) and sinomenine (10-9-10-4 M) at 25°C for 60 min. Nonspecific binding was defined with 10 μM naloxone. Bound ligand was separated by filtration, and radioactivity was measured. Sinomenine displaced [3H]-diprenorphine with moderate affinity, indicating μ-receptor interaction [2]
- NF-κB activity assay: MDA-MB-231 cells were transfected with NF-κB-luciferase reporter plasmid. After treatment with sinomenine (50 μM) and IL-4 (10 ng/mL), luciferase activity was measured. Sinomenine reduced IL-4-induced luciferase activity by 58%, indicating NF-κB inhibition [1] |
| Cell Assay |
- Breast cancer invasion assay: MDA-MB-231 cells were seeded in Matrigel-coated transwell inserts with sinomenine (10-100 μM) in serum-free medium. After 24 h, invaded cells were fixed, stained, and counted. Sinomenine (100 μM) reduced invasion by 62% vs. control [1]
- Glioma autophagy assay: U87 cells were treated with sinomenine (50-200 μM) for 24 h. Autophagosomes were visualized by LC3 immunofluorescence staining. Western blot analysis showed increased LC3-II/LC3-I ratio (2.8-fold at 100 μM) and Beclin-1 expression, confirming autophagy activation [6] - Microglia cytokine assay: Primary rat microglia were pretreated with sinomenine (10-50 μM) for 1 h, then stimulated with LPS (1 μg/mL) for 24 h. TNF-α and IL-1β levels in supernatants were measured by ELISA, showing 40-60% reduction at 50 μM [3] In this investigation, the MDA-MB-231 human triple-negative and 4T1 mouse breast cancer cell lines are employed. The cells are grown in 24-well plates at 3.5 104 cells per well for the experiments. According to the manufacturer's recommendations, cell proliferation is assessed after being incubated for 24 or 48 hours in medium containing various concentrations of Sinomenine[1]. |
| Animal Protocol |
In this experiment, male Sprague-Dawley rats weighing between 250 and 300 g are employed. Different doses of Sinomenine (10 to 40 mg/kg) are given 1 day after surgery, and the paw withdrawal threshold is then measured every 30 minutes for 4 hours to determine the duration of action of the acute Sinomenine study. Three hours after the daily drug treatment in the study involving Sinomenine, a mechanical hyperalgesia test is conducted. In studies involving antagonists, antagonists were administered 10 min before 40 mg/kg Sinomenine administration[3].
- Neuropathic pain model (CCI): Male rats underwent sciatic nerve ligation. From day 7 post-surgery, sinomenine (10-40 mg/kg) was administered intraperitoneally once daily. PWT (von Frey filaments) and PWL (hot plate, 52°C) were measured on days 7, 10, 14 [4] - Glioma xenograft model: Nude mice were subcutaneously injected with U87 cells (1×10⁶). When tumors reached 100 mm³, sinomenine hydrochloride (50 mg/kg) or vehicle (saline) was injected intraperitoneally every other day. Tumor volume was measured twice weekly, and mice were euthanized on day 21 for tissue analysis [6] - Inflammatory pain model: Mice received CFA (20 μL, intraplantar) on day 0. Sinomenine (20-80 mg/kg) was administered orally on days 1-7. Thermal hyperalgesia was assessed using a radiant heat source, measuring paw withdrawal time [3] |
| Toxicity/Toxicokinetics |
5459308 mouse LD50 oral 580 mg/kg BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY); BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD Yaoxue Xuebao. Acta Pharmaceutica Sinica. Pharmaceutical Journal., 10(673), 1963 [PMID:14097213]
5459308 mouse LD50 intraperitoneal 285 mg/kg BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION Yaoxue Xuebao. Acta Pharmaceutica Sinica. Pharmaceutical Journal., 8(177), 1960 |
| References |
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| Additional Infomation |
Sinomenine is a morphinane alkaloid.
Sinomenine has been reported in Stephania cephalantha, Sinomenium acutum, and other organisms with data available. Sinomenine is an alkaloid isolated from the root of Sinomenium acutum with immunomodulatory and potential anti-angiogenic and activities. Although the mechanism of action remains to be fully elucidated, sinomenine appears to inhibit endothelial proliferation mediated through basic fibroblast growth factor (bFGF), which may contribute to its anti-angiogenic effect. In Chinese medicine, this agent has a long track-record in treating arthritis, which is accounted by its ability to inhibit proliferation of synovial fibroblasts and lymphocytes. In addition, sinomenine has been shown to suppress expressions of genes involved in inflammation and apoptosis, such as interleukin-6, a pleiotropic inflammatory cytokine and JAK3 (Janus kinase 3), Daxx (death-associated protein 6), plus HSP27 (heat shock 27kDa protein 1), respectively. - Sinomenine is an alkaloid isolated from the Chinese herb Sinomenium acutum, traditionally used for anti-inflammatory and analgesic effects [3][4] - Its mechanisms include μ-opioid receptor activation (analgesia), NF-κB inhibition (anti-invasion in breast cancer), STAT3 suppression, and ROS-mediated autophagy induction (glioma growth inhibition) [1][2][5][6] - The hydrochloride salt (sinomenine hydrochloride) shows improved water solubility and is used in in vivo studies for better bioavailability [6] |
| Molecular Formula |
C19H23NO4
|
|---|---|
| Molecular Weight |
329.3902
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| Exact Mass |
329.162
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| Elemental Analysis |
C, 69.28; H, 7.04; N, 4.25; O, 19.43
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| CAS # |
115-53-7
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| Related CAS # |
Sinomenine hydrochloride;6080-33-7
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| PubChem CID |
5459308
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
513.6±50.0 °C at 760 mmHg
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| Melting Point |
180ºC
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| Flash Point |
264.4±30.1 °C
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| Vapour Pressure |
0.0±1.4 mmHg at 25°C
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| Index of Refraction |
1.625
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| LogP |
1.25
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
24
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| Complexity |
562
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| Defined Atom Stereocenter Count |
3
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| SMILES |
O(C([H])([H])[H])C1C(C([H])([H])[C@@]23C4C(=C(C([H])=C([H])C=4C([H])([H])[C@@]([H])([C@@]2([H])C=1[H])N(C([H])([H])[H])C([H])([H])C3([H])[H])OC([H])([H])[H])O[H])=O
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| InChi Key |
INYYVPJSBIVGPH-QHRIQVFBSA-N
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| InChi Code |
InChI=1S/C19H23NO4/c1-20-7-6-19-10-14(21)16(24-3)9-12(19)13(20)8-11-4-5-15(23-2)18(22)17(11)19/h4-5,9,12-13,22H,6-8,10H2,1-3H3/t12-,13+,19-/m1/s1
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| Chemical Name |
(1R,9S,10S)-3-hydroxy-4,12-dimethoxy-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5,11-tetraen-13-one
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| Synonyms |
Sinomenine; Kukoline; Coculine; Sinomenine; 115-53-7; Kukoline; Cucoline; Coculine; Sabianine A; morphinan-6-one, 7,8-didehydro-4-hydroxy-3,7-dimethoxy-17-methyl-, (9alpha,13alpha,14alpha)-; 63LT81K70N; Cucoline
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: ~65 mg/mL (~197.3 mM)
Ethanol: ~65 mg/mL (~197.3 mM) 1M HCl (aqueous): 25 mg/mL (76.0 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.59 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 (7.59 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (7.59 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 | 3.0359 mL | 15.1796 mL | 30.3591 mL | |
| 5 mM | 0.6072 mL | 3.0359 mL | 6.0718 mL | |
| 10 mM | 0.3036 mL | 1.5180 mL | 3.0359 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05764304 | Not yet recruiting | Drug: Sinomenine Drug: Glucocorticoid |
Knee Osteoarthritis | Shanghai 6th People's Hospital | February 28, 2023 | Phase 3 |
| NCT00409071 | Completed | Drug: Cocculine® Drug: placebo |
Breast Cancer | Centre Leon Berard | September 2005 | Phase 3 |
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