| Size | Price | |
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| 500mg | ||
| 1g | ||
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Trodusquemine (formerly known as MSI-1436 and MSI-1436C), a natural product isolated from the dogfish shark Squalus acanthias, is a novel protein tyrosine phosphatase PTP-1B inhibitor. It has been evaluated as an obesity-fighting drug. Trodusquemine's activity is more targeted than that of current antianxiety drugs such as alprazolam, which calm excited neurons throughout the brain.
| Targets |
PTB-1B (IC50 = 1 μM); TC-PTP (IC50 = 224 μM)[1]
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| ln Vitro |
HepG2 cells treated with 10 µM MSI-1436 for 30 minutes did not show any phosphorylation of IRβ; however, when MSI-1436 was added to 100 nM insulin, p-IRβ rose eighteen times in comparison to untreated cells and eighteen times higher than treated cells. Insulin alone caused a threefold increase in cells. With a final IC50 value of 224 µM, MSI-1436's inhibitory effect on TCPTP is around two logs lower than its inhibitory effect on PTP1B activity [1]. In F11 neuronal cells, MSI-1436 (trodusquemine, 10 μM) reinstates ERK phosphorylation of the mGluR1/5 agonist DHPG. In LMO4KO BLA neurons, MSI-1436 (10 uM) recovers DHPG-induced holding currents and restores DSI [2]. In cultured neuronal cells, MSI-1436 (0.1-100 µM) inhibits PTP1B activity and displays insulin-mimicking properties [3].
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| ln Vivo |
In mice, MSI-1436 (10 mg/kg, i.p.) decreased the amount of fat in white adipose tissue, adipocyte size, and total body fat content. It also caused obesity-dependent body weight. MSI-1436 treatment significantly reduced plasma insulin levels. MSI-1436 (10 mg/kg, i.p.) increases STAT-3 phosphorylation 2.7-fold and p-IRβ three-fold when combined with 100 U/kg insulin compared to rats treated with insulin alone [1]. MSI-1436 (Trodusquemine) exerts anxiolytic effects by restoring endocannabinoid (eCB) signaling within the amygdala [2]. MSI-1436 (5 mg/kg, i.p.) has antidiabetic effects in diabetic mice and is sufficient to inhibit food intake and cause weight loss in CD1 mice [3].
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| Enzyme Assay |
Kinase assays[1]
Human kinases activities were measured using KINOMEscan. In brief, 256 DNA-tagged kinases, ligand affinity beads, and MSI-1436 (10 µmol/l) were incubated at room temperature, washed, and then eluted. Phage titer in the eluates was quantitated by real-time quantitative PCR.[1]
Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling, interfering with its control of glucose homeostasis and metabolism. PTP1B activity is elevated in obesity and type 2 diabetes and is a major cause of insulin resistance. Trodusquemine (MSI-1436) is a "first-in-class" highly selective inhibitor of PTP1B that can cross the blood-brain barrier to suppress feeding and promote insulin sensitivity and glycemic control. Trodusquemine is a naturally occurring cholestane that can be purified from the liver of the dogfish shark, Squalus acanthias, but it can also be manufactured synthetically by a fairly laborious process that requires several weeks. Here, we tested a novel easily and rapidly (2 days) synthesized polyaminosteroid derivative (Claramine) containing a spermino group similar to Trodusquemine for its ability to inhibit PTP1B. Like Trodusquemine, Claramine displayed selective inhibition of PTP1B but not its closest related phosphatase TC-PTP. In cultured neuronal cells, Claramine and Trodusquemine both activated key components of insulin signaling, with increased phosphorylation of insulin receptor-β (IRβ), Akt and GSK3β. Intraperitoneal administration of Claramine or Trodusquemine effectively restored glycemic control in diabetic mice as determined by glucose and insulin tolerance tests. [3] |
| Cell Assay |
F11 neuronal cells (a chimeric cell line of the mouse neuroblastoma cell line N18TG-2 fused with embryonic rat dorsal-root ganglion neurons) can be easily cultured without special coating on the plates. F11 cells were grown and maintained as described previously.[3]
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| Animal Protocol |
In vivo voltammetry[1]
Adult Sprague–Dawley rats (n = 12) were anesthetized (100 mg/kg ketamine, 50 mg/kg xylazine), cannulas placed in the nucleus accumbens core, and a stimulating electrode was placed in the ventral tegmental area. After recovery, dopamine was electrically evoked (stimulation train: 60 Hz, 24 p, 1.2 µA) every 5 min and measured using fast-scan cyclic voltammetry. Baseline dopamine was recorded before intraperitoneal injection of MSI-1436 (10 mg/kg), nomifensine (7 mg/kg), or saline. Peak dopamine concentration and time to decay to 37% (τ) were recorded over a 60-min period after dose and expressed as percent change from baseline. Fast-scan cyclic voltammetry was performed in both awake and behaving rats as described previously.
Tail suspension test[1] Mice (CD1, n = 6/group; Charles River Laboratories, Kingston, NY) were administered MSI-1436 (5 or 10 mg/kg, IP), norepinephrine reuptake inhibitor (positive control) (20 mg/kg desipramine HCl in 0.1% DMSO, IP), or vehicle. After 30 min, mice were suspended by their tail in a sensory controlled environment, and duration of immobility during a 6-min period was recorded by three independent observers masked to treatments. Glucose tolerance test (GTT) and insulin tolerance test (ITT)[3] 3.5-month-old male mice received intraperitoneal injection of Claramine or Trodusquemine dissolved in saline (5 mg/kg body weight) 24 h or 48 h prior to GTT or ITT, respectively. Mice were fasted overnight (∼16 h) with access to water prior to GTT at 10:00. Basal blood glucose sampled from the saphenous vein was measured using a standard glucometer prior to and after mice received a glucose bolus (2 g/kg body weight of 20% d-glucose) by intraperitoneal injection as described previously.[3] A separate cohort of mice was fasted for 4 h prior to ITT, performed between 14:00 and 17:00. Human recombinant insulin (Sigma; Cat. #91077C), diluted in sterile saline was administered by intraperitoneal injection at 0.75 U/kg and blood glucose levels were monitored as above.[3] |
| References |
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| Additional Infomation |
Trodusquemine is a bile acid.
Trodusquemine, a spermine metabolite of cholesterol, is a naturally occurring aminosterol that inhibits protein tyrosine phosphatase 1B. It has demonstrated the ability to stimulate regeneration of heart and multiple other tissues in animal models. Trodusquemine has been reported in Squalus acanthias with data available. Trodusquemine is a naturally-occurring cholestane and non-competitive, allosteric inhibitor of protein tyrosine phosphatase 1B (PTP1B), with potential hypoglycemic, anti-diabetic, anti-obesity, and antineoplastic activities. Upon administration, trodusquemine selectively targets and inhibits PTP1B, thereby preventing PTP1B-mediated signaling. This prevents the dephosphorylation of the insulin receptor, which improves insulin signaling and insulin sensitivity, and decreases blood glucose levels. In susceptible cancer cells, inhibition of PTP1B causes a reduction of tumor cell proliferation. In addition, as trodusquemine can cross the blood-brain barrier (BBB), it centrally suppresses appetite and causes weight loss. PTP1B, a tyrosine phosphatase, is elevated in certain cancer cells; it is specifically upregulated in human epidermal growth factor receptor 2 (HER2)-driven cancers where it promotes cell growth, and is correlated with a poor prognosis and increased metastatic potential. In diabetes, PTP1B upregulation plays a major role in insulin resistance. Drug Indication Investigated for use/treatment in obesity and diabetes mellitus type 2. Mechanism of Action Trodusquemine is a spermine metabolite of cholesterol which possibly acts on the paraventricular nucleus in the hypothalamus. Trodusquemine suppresses feeding, prevents reduction in energy expenditure, causes hormonal changes, and induces patterns of neuropeptide expression normally associated with weight loss. Trosdusquemine enhances insulin sensitivity through inhibition of protein tyrosine phostphatase 1B centrally and peripherally (PTP-1B), dopamine and norepinephrine reuptake, an ion transport modulator and a downregulator of Agouti-related peptide (AgRP) and neuropeptide Y (NPY) expression. |
| Molecular Formula |
C37H72N4O5S
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|---|---|
| Molecular Weight |
685.066
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| Exact Mass |
684.522
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| Elemental Analysis |
C, 64.87; H, 10.59; N, 8.18; O, 11.68; S, 4.68
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| CAS # |
186139-09-3
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| Related CAS # |
MSI-1436 lactate;1309370-86-2;MSI-1701;390808-64-7
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| PubChem CID |
9917968
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| Appearance |
White to yellow solid powder
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| Density |
1.1±0.1 g/cm3
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| Index of Refraction |
1.548
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| LogP |
6.24
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
20
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| Heavy Atom Count |
47
|
| Complexity |
1040
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| Defined Atom Stereocenter Count |
11
|
| SMILES |
C[C@H](CC[C@H](C(C)C)OS(=O)(=O)O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2[C@@H](C[C@@H]4[C@@]3(CC[C@@H](C4)NCCCNCCCCNCCCN)C)O)C
|
| InChi Key |
WUJVPODXELZABP-FWJXURDUSA-N
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| InChi Code |
InChI=1S/C37H72N4O5S/c1-26(2)34(46-47(43,44)45)13-10-27(3)30-11-12-31-35-32(15-17-37(30,31)5)36(4)16-14-29(24-28(36)25-33(35)42)41-23-9-22-40-20-7-6-19-39-21-8-18-38/h26-35,39-42H,6-25,38H2,1-5H3,(H,43,44,45)/t27-,28-,29+,30-,31+,32+,33-,34-,35+,36+,37-/m1/s1
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| Chemical Name |
(3R,6R)-6-((3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptan-3-yl hydrogen sulfate
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| Synonyms |
Aminosterol 1436; Aminosterol-1436; MSI1436;Trodusquemine; MSI-1436; 186139-09-3; KKC12PIF16; CHEMBL508583; Produlestan; Trodulamine; Trodusquemine [USAN]; MSI-1436; MSI 1436; MSI1436C; MSI-1436C; MSI 1436C; Aminosterol1436
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 1.4597 mL | 7.2985 mL | 14.5970 mL | |
| 5 mM | 0.2919 mL | 1.4597 mL | 2.9194 mL | |
| 10 mM | 0.1460 mL | 0.7299 mL | 1.4597 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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