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Purity: ≥98%
ML204 HCl is a novel, potent, and selective TRPC4 (Transient receptor potential canonical) channel inhibitor identified from high throughput fluorescent screen of 305,000 compounds of the Molecular Libraries Small Molecule Repository for inhibitors that blocked intracellular Ca(2+) rise in response to stimulation of mouse TRPC4β by μ-opioid receptors. ML204 inhibited TRPC4β-mediated intracellular Ca(2+) rise with an IC(50) value of 0.96 μm and exhibited 19-fold selectivity against muscarinic receptor-coupled TRPC6 channel activation. In whole-cell patch clamp recordings, ML204 blocked TRPC4β currents activated through either μ-opioid receptor stimulation or intracellular dialysis of guanosine 5'-3-O-(thio)triphosphate (GTPγS), suggesting a direct interaction of ML204 with TRPC4 channels rather than any interference with the signal transduction pathways. Selectivity studies showed no appreciable block by 10-20 μm ML204 of TRPV1, TRPV3, TRPA1, and TRPM8, as well as KCNQ2 and native voltage-gated sodium, potassium, and calcium channels in mouse dorsal root ganglion neurons. In isolated guinea pig ileal myocytes, ML204 blocked muscarinic cation currents activated by bath application of carbachol or intracellular infusion of GTPγS, demonstrating its effectiveness on native TRPC4 currents. Therefore, ML204 represents an excellent novel tool for investigation of TRPC4 channel function and may facilitate the development of therapeutics targeted to TRPC4.
ln Vitro |
ML204 hydrochloride shows 19-fold selectivity against muscarinic receptor-coupled TRPC6 channel activation and inhibits TRPC4β-mediated intracellular Ca2+ increase with an IC50 value of 0.96 μM (HEK293 cells)[1]. ML204 hydrochloride inhibits TRPC4β activity that is triggered by endogenous M3-like muscarinic receptors stimulating Gq/11 or Gi/o activation by μ-opioid, 5HT1A serotonin, and M2 muscarinic receptors[1]. LPS-induced TRPC5 channel activity is inhibited by ML204 hydrochloride[3].
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ln Vivo |
In LPS-injected mice, ML204 hydrochloride (1 mg/kg; sc; twice a day; for 5 days) reduces peritoneal leukocyte counts and cytokines and causes mortality linked to worsened hypothermia[4].
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Animal Protocol |
Animal/Disease Models: Nonfasted male C57BL/6 (2 -3 months)[4]
Doses: 1 mg/kg Route of Administration: subcutaneous (sc) injection, twice a day, for 5 days (prior to LPS injection) Experimental Results: Induces mortality associated with increased hypothermia in mice with LPS-induced systemic inflammatory response. |
References |
[1]. Miller M, et al. Identification of ML204, a novel potent antagonist that selectively modulates native TRPC4/C5 ion channels. J Biol Chem. 2011 Sep 23;286(38):33436-46.
[2]. Miller MR, et al. Novel Chemical Inhibitor of TRPC4 Channels. Probe Reports from the NIH Molecular Libraries Program. [3]. Thomas Schaldecker, et al. Inhibition of the TRPC5 ion channel protects the kidney filter. J Clin Invest. 2013 Dec 2; 123(12): 5298–5309. [4]. Domingos M S Pereira, et al. Transient Receptor Potential Canonical Channels 4 and 5 Mediate Escherichia coli-Derived Thioredoxin Effects in Lipopolysaccharide-Injected Mice. Oxid Med Cell Longev. 2018 Jun 10;2018:4904696. |
Molecular Formula |
C15H19CLN2
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Molecular Weight |
262.78
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CAS # |
2070015-10-8
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Related CAS # |
5465-86-1;2070015-10-8 (HCl);
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SMILES |
CC1=CC(N2CCCCC2)=NC3=CC=CC=C13.[H]Cl
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Chemical Name |
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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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) |
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Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 3.8055 mL | 19.0273 mL | 38.0546 mL | |
5 mM | 0.7611 mL | 3.8055 mL | 7.6109 mL | |
10 mM | 0.3805 mL | 1.9027 mL | 3.8055 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.
Fluorescent assay for TRPC4β channels used to identify and characterize ML204.J Biol Chem.2011 Sep 23;286(38):33436-46. td> |
Activation of heterologously expressed TRPC4 channels and its inhibition by ML204.J Biol Chem.2011 Sep 23;286(38):33436-46. td> |
ML204 blocks TRPC4 current elicited by different activation mechanisms. td> |