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Purity: ≥98%
Yoda 1 (GlyT2-IN-1) is a novel and potent agonist of Piezo1 which is the mechanotransduction channel. Yoda 1 activates purified Piezo1 channels. Yoda1 works by eliciting Ca2+ flux in Piezo1- but not vector-transfected cells.
| Targets |
ERK1/2
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|---|---|
| ln Vitro |
Akt and ERK1/2 are activated in a Piezo1-independent manner by Yoda1 (0–6 μM, 5 min) [2]. Rac1 activation is inhibited by Yoda1 (1.5 μM, 5 min) [3].
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| ln Vivo |
Secondary brain injury after intracerebral hemorrhage (ICH) is the main cause of poor prognosis in ICH patients, but the underlying mechanisms remain less known. The involvement of Piezo1 in brain injury after ICH was studied in a mouse model of ICH. ICH was established by injecting autologous arterial blood into the basal ganglia in mice. After vehicle, Piezo1 blocker, GsMTx4, Piezo1 activator, Yoda-1, or together with mannitol (tail vein injection) was injected into the left lateral ventricle of mouse brain, Piezo1 level and the roles of Piezo1 in neuronal injury, brain edema, and neurological dysfunctions after ICH were determined by the various indicated methods. Piezo1 protein level in neurons was significantly upregulated 24 h after ICH in vivo (human and mice). Piezo1 protein level was also dramatically upregulated in HT22 cells (a murine neuron cell line) cultured in vitro 24 h after hemin treatment as an in vitro ICH model. GsMTx4 treatment or together with mannitol significantly downregulated Piezo1 and AQP4 levels, markedly increased Bcl2 level, maintained more neurons alive, considerably restored brain blood flow, remarkably relieved brain edema, substantially decreased serum IL-6 level, and almost fully reversed the neurological dysfunctions at ICH 24 h group mice. In contrast, Yoda-1 treatment achieved the opposite effects. In conclusion, Piezo1 plays a crucial role in the pathogenesis of brain injury after ICH and may be a target for clinical treatment of ICH.[4]
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| Enzyme Assay |
384-well format [1]
2 days after transfection, the cells were washed with assay buffer (1× HBSS, 10 mM HEPES, pH7.4) using a ELx405 CW plate washer. Cells were incubated with assay buffer containing 4 μM Fluo3 and 0.04% Pluronic F-127 for ∼60 min and then washed again with assay buffer. Fluorescence was monitored on a fluorescent imaging plate reader (FLIPR) Tetra. To chelate extracellular calcium (1× HBSS contains 1.26 mM CaCl2), 2 mM ethylene glycol tetraacetic acid (EGTA) was added to the cells 1 min before addition of the indicated Yoda1 concentration in presence of 2 mM EGTA. To deplete intracellular calcium, 7.5 μM thapsigargin was added 15 min before Yoda1 addition. A 10-mM stock solution of Yoda1 in dimethyl sulfoxide (DMSO) was used resulting in a maximum of 1% DMSO in the assay. Concentration-response curves were fitted using a sigmoidal dose–response at variable slope.[1] 1536-well high-throughput screen format [1] With objective of identifying either a Piezo1 or Piezo2 agonist, we co-transfected cells with mPiezo1 and mPiezo2 cDNA at equal amounts. 2 days after, transfection cells were incubated with Calcium5 according to manufacturer's instruction and fluorescence was monitored on FLIPR Tetra. About 3.25 million compounds from the LMW Novartis screening library, which includes public domain and proprietary drug-like molecules, were screened at a concentration of 5 μM. Approximately 9000 hits, as defined by 50% activation above DMSO control wells, were selected for retesting in co-transfected cells as well as individual Piezo1 and 2 transfection and control cells. From this, Yoda1 was identified as a potential Piezo1 activator and selected for further study. |
| Cell Assay |
Western Blot analysis
Cell Types: human coronary artery endothelial cells (HCAEC) [2], A431 cells [3] Tested Concentrations: 0, 1.5, 3.0 and 6.0 μM Incubation Duration: 5 minutes Experimental Results: Induced Akt and ERK1/2 activation, and increased Phosphorylation levels of Akt and ERK1/2 were dose-dependent. Inhibits EGF-induced increase in Rac1-GTP amount and inhibits Rac1 activation |
| Animal Protocol |
Inhibition or activation of Piezo1 after intracerebral hemorrhage (ICH) in mice[4]
The effects of Piezo1 blocker, GsMTx4, and Piezo1 activator, Yoda-1, on brain edema and neurological dysfunctions after ICH were studied in 27 mice. The mice were divided into five groups, (1) control (n = 6), (2) ICH 24 h (n = 6), (3) ICH 72 h (n = 3), (4) ICH 24 h + GsMTx4 (3 μM, n = 6), and (5) ICH 24 h + Yoda-1 (10 μM, n = 6). Please refer to the Supplementary Materials and Methods file (Appendix A Supplementary data) for details. |
| References | |
| Additional Infomation |
Yoda 1 is a member of the class of thiadiazoles that is 1,3,4-thiadiazole substituted by pyrazin-2-yl and (2,6-dichlorobenzyl)sulfanediyl groups at positions 2 and 5, respectively. It is a selective activator of mechanosensitive channel piezo1. It has a role as a glycine transporter 2 inhibitor and a piezo1 agonist. It is an aromatic compound, a member of pyrazines, a member of thiadiazoles, an organic sulfide and a dichlorobenzene.
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| Molecular Formula |
C13H8CL2N4S2
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|---|---|
| Molecular Weight |
355.265417098999
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| Exact Mass |
353.956
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| Elemental Analysis |
C, 43.95; H, 2.27; Cl, 19.96; N, 15.77; S, 18.05
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| CAS # |
448947-81-7
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| Related CAS # |
448947-81-7;
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| PubChem CID |
2746822
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| Appearance |
White to light yellow solid powder
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| Density |
1.6±0.1 g/cm3
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| Boiling Point |
538.4±60.0 °C at 760 mmHg
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| Flash Point |
279.4±32.9 °C
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| Vapour Pressure |
0.0±1.4 mmHg at 25°C
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| Index of Refraction |
1.714
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| LogP |
4.89
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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 |
4
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| Heavy Atom Count |
21
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| Complexity |
329
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
BQNXBSYSQXSXPT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C13H8Cl2N4S2/c14-9-2-1-3-10(15)8(9)7-20-13-19-18-12(21-13)11-6-16-4-5-17-11/h1-6H,7H2
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| Chemical Name |
2-[5-(2,6-Dichloro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-pyrazine
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| Synonyms |
Yoda1; Yoda-1; GlyT2-IN-1; YODA-1; 2-((2,6-dichlorobenzyl)thio)-5-(pyrazin-2-yl)-1,3,4-thiadiazole; TW6GF9RW6S; 2-[(2,6-dichlorophenyl)methylsulfanyl]-5-pyrazin-2-yl-1,3,4-thiadiazole; Yoda 1
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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 : ~15.62 mg/mL (~43.97 mM)
Ethanol : ~5 mg/mL (~14.07 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.56 mg/mL (4.39 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 15.6 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 2: ≥ 1.56 mg/mL (4.39 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 15.6 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 | 2.8148 mL | 14.0738 mL | 28.1476 mL | |
| 5 mM | 0.5630 mL | 2.8148 mL | 5.6295 mL | |
| 10 mM | 0.2815 mL | 1.4074 mL | 2.8148 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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