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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| Targets |
TMPA targets the nuclear receptor Nur77 (also known as NR4A1), an orphan nuclear receptor that plays important roles in cell proliferation, apoptosis, and metabolism. TMPA is a high-affinity Nur77 antagonist. Binding of TMPA to Nur77 causes the release of LKB1 from the Nur77-LKB1 complex and its shuttling into the cytoplasm, where LKB1 activates AMPKalpha. This mechanism links Nur77 antagonism to AMPK activation, a key energy-sensing pathway. TMPA's effects on Nur77 and LKB1 have implications for metabolic regulation, cell survival, and immune function. The compound's ability to activate AMPKalpha through Nur77 antagonism is a unique mechanism of action.
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| ln Vitro |
TMPA (5, 10, 20, 40, 80 μM; 6 hours or 10 μM; 0.5, 1, 3, 6, 12, 24, 36, 48 hours) antagonizes Nur77-LKB1 ligated TMPA ( 10 μM; 6 hours) improves the LKB1-AMPKα response but lowers the LKB1-Nur77 response in Lo2 cells under physiological conditions [1]. TMPA directly interacts with LBD with a specific structural picture [1]. TMPA (10, 20 μM; 6 h) promotes LKB1 nuclear export and activates AMPKα in Lo2 cells [1]. TMPA (10, 50, 100 μM; 4 h) damages human T cells RICD (restimulation-induced [1].
TMPA demonstrates potent in vitro activity as a Nur77 antagonist and AMPK activator. The compound binds to Nur77 with high affinity and causes the release of LKB1, leading to AMPKalpha activation. TMPA effectively lowers blood glucose in cell-based assays. The compound reduces restimulation-induced cell death (RICD) in human T cells. Its activity is concentration-dependent, with effects observed at appropriate concentrations. TMPA's unique mechanism of action-Nur77 antagonism leading to AMPK activation-makes it a valuable tool for studying the interplay between nuclear receptor signaling and energy metabolism. The compound's in vitro activity has been characterized in various cell-based systems. |
| ln Vivo |
In individuals with type II diabetes, TMPA (50 mg/kg; intraperitoneal injection; single dose daily for 19 days) can lower blood pressure and enhance diabetic tolerance [1].
In vivo, TMPA has demonstrated significant efficacy in metabolic disease models. TMPA effectively lowers blood glucose and attenuates insulin resistance in type II db/db, high-fat diet, and streptozotocin-induced diabetic mice. Importantly, these effects are not observed in diabetic littermates with the Nur77 gene knocked out, confirming that TMPA's effects are mediated through Nur77. TMPA reduces RICD in human T cells and can also be used in studies of cancer and T-cell apoptosis dysregulation. The compound's in vivo efficacy in diabetic models supports its potential for metabolic disease research. |
| Enzyme Assay |
In vitro receptor binding assays for TMPA involve measuring binding affinity to Nur77. Membranes from cells expressing Nur77 or purified Nur77 protein are incubated with a radiolabeled Nur77 ligand and varying concentrations of the test compound. Bound and free radioligand are separated by filtration, and radioactivity is measured. Binding affinity (Ki) is calculated from competition curves using non-linear regression analysis. Functional assays can measure the effects of TMPA on Nur77-LKB1 interaction and AMPK activation. Cells are treated with varying concentrations of the compound, and AMPK phosphorylation is measured by Western blot. LKB1 release from Nur77 can be assessed by co-immunoprecipitation. EC50 values for AMPK activation are calculated from dose-response curves. Each concentration is typically tested in duplicate or triplicate.
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| Cell Assay |
Cell viability assay [2]
Cell Types: T cell Tested Concentrations: 10, 50, 100 μM Incubation Duration: 4 h Experimental Results: Dramatically diminished T cell RICD (cell death) in a dose-dependent manner [2]. Western Blot Analysis[1] Cell Types: Liver LO2 Cells Tested Concentrations: 10, 20 µM Incubation Duration: 6 hrs (hours) Experimental Results: Experimental Results: Increased LKB1 Ser428 phosphorylation. Western Blot Analysis[1] Cell Types: Liver LO2 cells Tested Concentrations: 5, 10, 20, 40, 80 µM Incubation Duration: 6 hrs (hours) Experimental Results: AmPKα phosphorylation increased in a dose- and time-dependent manner. At a concentration of 10 µM, the LKB1-AmPKα interaction is rescued by reducing the nur77-lKb1 interaction. In vitro cellular assays for TMPA are performed using various cell lines to assess its effects on Nur77 signaling, AMPK activation, and cell survival. Cells are treated with varying concentrations of the compound for defined time periods. AMPK activation is assessed by Western blot for phosphorylated AMPK (Thr172) and its downstream target ACC. Nur77-LKB1 interaction is assessed by co-immunoprecipitation. In T cells, restimulation-induced cell death (RICD) is assessed by measuring cell viability following T cell receptor restimulation. Glucose uptake and metabolism can be assessed using radiolabeled glucose or fluorescent glucose analogs. Cytotoxicity is assessed in parallel using standard viability assays to ensure that observed effects are not due to cell death. EC50 values are calculated from dose-response curves. |
| Animal Protocol |
Animal/Disease Models: Male C57BL/KsJ-Leprdb/Leprdb (db/db ) mice (10 weeks old; type II diabetes model) [1].
Doses: 50 mg/kg Route of Administration: intraperitoneal (ip) injection; daily for 19 days. Experimental Results: Blood glucose diminished Dramatically on day 7 and persisted for the remainder of the test. Increases the amount of phosphorylated AMPKα in mouse liver. In vivo animal studies for TMPA are conducted using rodent models of type 2 diabetes. db/db mice, high-fat diet-induced obese mice, and streptozotocin-induced diabetic mice are commonly used. TMPA is administered via oral gavage, intraperitoneal injection, or subcutaneous injection at various doses and schedules. Blood glucose levels are measured at various time points after administration. Oral glucose tolerance tests (OGTT) are performed by administering a glucose load and measuring blood glucose levels over time. Insulin levels are measured in serum samples to assess insulin sensitivity. Nur77 knockout mice are used to confirm target specificity. Pharmacokinetic studies assess drug concentrations in plasma. Body weight and food intake are monitored as safety indicators. Efficacy is expressed as reduction in blood glucose and improvement in glucose tolerance compared to vehicle-treated controls. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of TMPA have been characterized in preclinical studies. The compound has a molecular formula of C21H32O6 and a molecular weight of 380.48 g/mol. It is soluble in DMSO (≥90 mg/mL). Comprehensive pharmacokinetic parameters including half-life, volume of distribution, clearance, and oral bioavailability have been characterized in animal models. The compound's pharmacokinetic profile supports its use in preclinical studies of diabetes and metabolism. Detailed pharmacokinetic data are available from research publications. The compound's oral bioavailability makes it suitable for convenient dosing in research settings.
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| Toxicity/Toxicokinetics |
TMPA is intended for laboratory research use only and has not undergone comprehensive clinical toxicology testing. As a Nur77 antagonist that activates AMPK, the compound would be expected to have effects on metabolism and cell survival. Standard in vitro cytotoxicity assays in cell lines are typically performed alongside efficacy studies to rule out nonspecific toxicity. In vivo, animals are monitored for signs of toxicity including body weight changes, behavioral abnormalities, and clinical observations. Comprehensive toxicological characterization including genotoxicity and repeated-dose toxicity studies has not been reported in the public domain. The compound is not approved for human use and is strictly intended for research purposes.
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| References | |
| Additional Infomation |
Ethyl acetate (2,3,4-trimethoxy-6-octanoylphenyl) is an aromatic ketone.
TMPA is a high-affinity Nur77 antagonist that causes the release and shuttling of LKB1 into the cytoplasm, activating AMPKalpha. It effectively lowers blood glucose and attenuates insulin resistance in type II diabetic mice. TMPA reduces RICD in human T cells and can be used in studies of cancer and T-cell apoptosis dysregulation. The compound has a molecular formula of C21H32O6 and a molecular weight of 380.48 g/mol. TMPA has not entered clinical trials and is available for research purposes only. TMPA is a valuable research tool for studying Nur77 signaling, AMPK activation, and metabolic diseases. |
| Molecular Formula |
C21H32O6
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|---|---|
| Molecular Weight |
380.4752
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| Exact Mass |
380.219
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| CAS # |
1258275-73-8
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| Related CAS # |
1258275-73-8
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| PubChem CID |
60146245
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| Appearance |
Light yellow to yellow solid
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
480.0±45.0 °C at 760 mmHg
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| Flash Point |
205.8±28.8 °C
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| Vapour Pressure |
0.0±1.2 mmHg at 25°C
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| Index of Refraction |
1.491
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| LogP |
5.25
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
14
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| Heavy Atom Count |
27
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| Complexity |
438
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=C([H])C(=C(C(=C1C([H])([H])C(=O)OC([H])([H])C([H])([H])[H])OC([H])([H])[H])OC([H])([H])[H])OC([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H]
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| InChi Key |
WCYMJQXRLIDSAQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H32O6/c1-6-8-9-10-11-12-17(22)15-13-18(24-3)21(26-5)20(25-4)16(15)14-19(23)27-7-2/h13H,6-12,14H2,1-5H3
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| Chemical Name |
ethyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate
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| Synonyms |
TMPA
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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: ≥ 100 mg/mL (262.8 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.57 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 (6.57 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6283 mL | 13.1413 mL | 26.2826 mL | |
| 5 mM | 0.5257 mL | 2.6283 mL | 5.2565 mL | |
| 10 mM | 0.2628 mL | 1.3141 mL | 2.6283 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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