| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
GABAA; cytochrome P450 isoforms; CYP2A6/CYP2E1
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|---|---|
| ln Vitro |
In cells containing α1/β1/γ2 or α1/β2/γ2 subunits, chlormethiazole (1 mM) causes significant whole-cell currents in the absence of GABA [1]. In cells expressing α1/β1/η2 and α1/β2/η2, GABAA currents are stimulated, with EC50 values of 0.3 and 1.5 mM, respectively[1]. The effects of GABA were also boosted by low concentrations of clomethiazole (30 μM), which in fact tripled the efficacy. The IC50 values of clomethiazole for cytochrome P450, CYP2A6, and CYP2E1 in human liver were 24 μM and 42 μM, respectively, whereas the values for all other minimum bodies were greater than 300. μM[2].
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| Enzyme Assay |
The sedative clomethiazole (CMZ) has been used in Europe since the mid-1960s to treat insomnia and alcoholism. It has been previously demonstrated in clinical studies to reversibly inhibit human CYP2E1 in vitro and decrease CYP2E1-mediated elimination of chlorzoxazone. We have investigated the selectivity of CMZ inhibition of CYP2E1 in pooled human liver microsomes (HLMs). In a reversible inhibition assay of the major drug-metabolizing cytochrome P450 (P450) isoforms, CYP2A6 and CYP2E1 exhibited IC50 values of 24 µM and 42 µM, respectively with all other isoforms exhibiting values >300 µM. When CMZ was preincubated with NADPH and liver microsomal protein for 30 minutes before being combined with probe substrates, however, more potent inhibition was observed for CYP2E1 and CYP2B6 but not CYP2A6 or other P450 isoforms. The substantial increase in potency of CYP2E1 inhibition upon preincubation enables the use of CMZ to investigate the role of human CYP2E1 in xenobiotic metabolism and provides advantages over other chemical inhibitors of CYP2E1. The KI and kinact values obtained with HLM-catalyzed 6-hydroxylation of chlorzoxazone were 40 µM and 0.35 minute(-1), respectively, and similar to values obtained with recombinant CYP2E1 (41 µM, 0.32 minute(-1)). The KI and kinact values, along with other parameters, were used in a mechanistic static model to explain earlier observations of a profound decrease in the rate of chlorzoxazone elimination in volunteers despite the absence of detectable CMZ in blood.[2]
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| Cell Assay |
Clomethiazole is a gamma-aminobutyric acid (GABA)-mimetic agent with anticonvulsant, sedative and neuroprotective properties. The pharmacological actions of clomethiazole that underlie its functional profile have not been fully explored, but are known to result from an interaction with the GABA(A) receptor. Here, we present a quantitative electrophysiological study of clomethiazole action at human recombinant GABA(A) receptors. Whole-cell currents were recorded from murine L(tk-) cells stably transfected with either alpha1, beta1 and gamma 2 or alpha1, beta2 and gamma 2 GABA(A) receptor subunits. Clomethiazole directly activated GABA(A) currents in alpha1/beta1/gamma 2- and alpha1/beta2/gamma 2-containing cells, with EC(50) values of 0.3 and 1.5 mM, respectively. A low concentration of clomethiazole (30 micro M) also potentiated the action of GABA in both cell types, equivalent to a 3-fold increase in potency and up to 1.8-fold increase in maximal current. Both direct activation and gamma-aminobutyric acid potentiation are likely to contribute to the in vivo profile of clomethiazole.[1]
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| ADME/Pharmacokinetics |
Metabolism / Metabolites
Clomethiazole has known human metabolites that include NLA-715. |
| Toxicity/Toxicokinetics |
mouse LD50 oral 2110 mg/kg Journal of Medicinal Chemistry., 7(167), 1964
mouse LD50 intraperitoneal 190 mg/kg Acta Pharmaceutica Suecica., 8(39), 1971 [PMID:5575873] mouse LD50 intravenous 94 mg/kg Acta Pharmaceutica Suecica., 7(423), 1970 [PMID:5480082] |
| References | |
| Additional Infomation |
5-(2-chloroethyl)-4-methylthiazole is a member of thiazoles.
Clomethiazole is a well-established γ-aminobutyric acid (GABAA)-mimetic drug. It is a sedative and hypnotic that is widely used in treating and preventing symptoms of acute alcohol withdrawal. It is a drug which is structurally related to thiamine (vitamin B1) but acts like a sedative, hypnotic, muscle relaxant and anticonvulsant. It is also used for the management of agitation, restlessness, short-term insomnia and Parkinson's disease in the elderly. A sedative and anticonvulsant often used in the treatment of alcohol withdrawal. Chlormethiazole has also been proposed as a neuroprotective agent. The mechanism of its therapeutic activity is not entirely clear, but it does potentiate GAMMA-AMINOBUTYRIC ACID receptors response and it may also affect glycine receptors. Drug Indication Investigated for use/treatment in strokes. Mechanism of Action clomethiazole interacts with the GABAA receptor complex. It inhibits the binding of [35S]butyl-bicyclophosphorothionate (TBPS), an effect indicative of GABAA receptor-channel activation, by increasing the rate of [35S]TBPS dissociation and decreasing the binding affinity. Gamma-aminobutyric acid (GABA), acting at GABAA receptors, is the main fast inhibitory neurotransmitter in mammalian central nervous system |
| Molecular Formula |
C8H14CLNO6S3
|
|---|---|
| Molecular Weight |
351.831
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| Exact Mass |
511.974
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| Elemental Analysis |
C, 27.31; H, 4.01; Cl, 10.08; N, 3.98; O, 27.28; S, 27.34
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| CAS # |
1867-58-9
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| Related CAS # |
1867-58-9 (edisylate);533-45-9;6001-74-7 (HCl);
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| PubChem CID |
9892648
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.218g/cm3
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| Boiling Point |
245.8ºC at 760mmHg
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| Flash Point |
102.4ºC
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| Vapour Pressure |
1.07E-23mmHg at 25°C
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| LogP |
5.389
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
|
| Heavy Atom Count |
28
|
| Complexity |
328
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
C(S(O)(=O)=O)CS(O)(=O)=O.ClCCC1SC=NC=1C.ClCCC1SC=NC=1C
|
| InChi Key |
WFVBVWRCFZCWJU-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/2C6H8ClNS.C2H6O6S2/c2*1-5-6(2-3-7)9-4-8-5;3-9(4,5)1-2-10(6,7)8/h2*4H,2-3H2,1H3;1-2H2,(H,3,4,5)(H,6,7,8)
|
| Chemical Name |
5-(2-chloroethyl)-4-methyl-1,3-thiazole;ethane-1,2-disulfonic acid
|
| Synonyms |
Distraneurin; Clomethiazole edisylate; Clomethiazole edisylate; 1867-58-9; Chlormethiazole edisylate; Heminevrin; Hemithiamine; Clomethiazole ethane-1,2-disulfonate; Clomethiazol edisilat; SCTZ; Chlormethiazole edisylate
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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 | 2.8423 mL | 14.2114 mL | 28.4228 mL | |
| 5 mM | 0.5685 mL | 2.8423 mL | 5.6846 mL | |
| 10 mM | 0.2842 mL | 1.4211 mL | 2.8423 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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