| Size | Price | Stock | Qty |
|---|---|---|---|
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg |
|
||
| Other Sizes |
| Targets |
GABAA; cytochrome P450 isoforms; CYP2A6/CYP2E1
Chlormethiazole hydrochloride targets the GABAA receptor complex. As a GABAA agonist and positive allosteric modulator, it enhances the activity of the neurotransmitter GABA, which helps to reduce brain activity and promote relaxation. It inhibits the binding of [35S]TBPS by increasing the dissociation rate and decreasing its binding affinity, an effect that indicates activation of the GABAA receptor channel. The compound also acts as a glycine receptor modulator and inhibits cytochrome P450 isoforms CYP2A6 and CYP2E1. |
|---|---|
| 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].
In vitro, Chlormethiazole hydrochloride is a potent GABAA agonist and glycine receptor modulator. It inhibits the binding of [35S]TBPS by increasing the dissociation rate and decreasing its binding affinity, indicating activation of the GABAA receptor channel. The compound inhibits cytochrome P450 isoforms CYP2A6 and CYP2E1 in human liver microsomes. It has neuroprotective effects and prevents the degeneration of serotonergic nerve terminals induced by MDMA. |
| ln Vivo |
In vivo, Chlormethiazole hydrochloride is an orally active anticonvulsant agent with potential for treating convulsive status epilepticus. It acts on the central nervous system to produce calming and sleep-inducing effects. The compound protects against neuronal death in the hippocampus in gerbils. Its anticonvulsant action is prevented by subconvulsive amounts of strychnine and aminophylline but not by bicuculline and picrotoxin. The compound is neuroprotective.
|
| 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]
In vitro receptor binding assays for Chlormethiazole hydrochloride involve measuring affinity for the GABAA receptor. Radioligand binding displacement studies are performed using [35S]TBPS as a probe. The compound's effect on dissociation rate and binding affinity is measured. Functional modulation is assessed by measuring GABA-induced chloride influx in electrophysiology assays. CYP2A6 and CYP2E1 inhibition is assessed using isoform-specific substrates in human liver microsomes. Assays are performed in appropriate buffer systems with positive controls such as known GABAA agonists. |
| 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]
In vitro cell-based assays for Chlormethiazole hydrochloride are conducted in neuronal cell lines or primary neurons. Cells are cultured in appropriate media and treated with the compound at varying concentrations. GABAA receptor activation is assessed by measuring chloride influx using fluorescent probes or patch-clamp electrophysiology. Neuroprotective effects are assessed in models of excitotoxicity or oxidative stress. Cell viability is assessed by standard assays. Experiments are performed in triplicate with appropriate positive and negative controls. |
| Animal Protocol |
Chlormethiazole hydrochloride in vivo studies are conducted in animal models of seizures and neurological disorders. Animals are treated with the compound via oral administration or injection. For anticonvulsant studies, seizure induction models such as pentylenetetrazole-induced seizures are used. Seizure severity and latency are monitored. For neuroprotection studies, animal models of neurodegeneration or ischemia are employed. The compound's protective effects against neuronal death are assessed. Animals are monitored for clinical signs. Tissues and blood samples are collected for histopathological and biochemical analysis at study endpoints. Studies are conducted in accordance with institutional animal care guidelines.
|
| ADME/Pharmacokinetics |
Metabolism / Metabolites
Chlorothiazine's known metabolites include NLA-715. Chlormethiazole hydrochloride (MW 198.11 g/mol, C6H9Cl2NS) is a synthetic thiazole derivative. It is a potent and orally active GABAA agonist. The compound is soluble in DMSO and other appropriate solvents. It is stable under recommended storage conditions. Chlormethiazole hydrochloride is a neuroprotective agent that prevents serotonergic nerve terminal degeneration. Pharmacokinetic parameters such as half-life, bioavailability, and tissue distribution have been characterized in preclinical and clinical studies. |
| Toxicity/Toxicokinetics |
The oral LD50 in mice was 2110 mg/kg, Journal of Medicinal Chemistry, 7(167), 1964. The intraperitoneal LD50 in mice was 190 mg/kg, Swedish Pharmaceutical Journal, 8(39), 1971 [PMID:5575873]. The intravenous LD50 in mice was 94 mg/kg, Swedish Pharmaceutical Journal, 7(423), 1970 [PMID:5480082].
Chlormethiazole hydrochloride is generally well-tolerated at therapeutic doses. The compound is a GABAA agonist with sedative and anticonvulsant effects. Its anticonvulsant action is prevented by strychnine and aminophylline. No significant adverse effects have been reported in the available literature at research-use concentrations. The compound is intended for research use only. Standard safety precautions should be followed when handling. Comprehensive toxicological evaluation is available from clinical use data. |
| References | |
| Additional Infomation |
5-(2-Chloroethyl)-4-methylthiazole belongs to the thiazole class of compounds. Chlorothiazole is a mature γ-aminobutyric acid (GABA) receptor agonist. It has sedative-hypnotic effects and is widely used to treat and prevent acute alcohol withdrawal symptoms. The structure of chlorothiazole is related to thiamine (vitamin B1), but its effects are similar to those of a sedative, hypnotic, muscle relaxant, and anticonvulsant. It is also used to treat agitation, restlessness, short-term insomnia, and Parkinson's disease in the elderly. Chlorothiazole is a commonly used sedative-anticonvulsant for the treatment of alcohol withdrawal. In addition, chlorothiazole is also believed to have neuroprotective effects. Its mechanism of action is not fully understood, but it does enhance the response of γ-aminobutyric acid (GABA) receptors and may also affect glycine receptors.
Drug Indications It has been studied for the treatment of stroke. Mechanism of Action Chlorothiazole interacts with the GABAA receptor complex. It inhibits the binding of [35S]TBPS by increasing the dissociation rate of [35S]butylbicyclic thiophosphate (TBPS) and decreasing its binding affinity, an effect that indicates activation of the GABAA receptor channel. γ-Aminobutyric acid (GABA), which acts on GABAA receptors, is a major fast-inhibitory neurotransmitter in the mammalian central nervous system. Chlormethiazole hydrochloride (Clomethiazole hydrochloride) is a potent and orally active GABAA agonist and positive allosteric modulator of the GABA-A receptor. It has neuroprotective, anticonvulsant, and sedative properties. The compound inhibits CYP2A6 and CYP2E1 and is used as an anticonvulsant agent. It protects against neuronal death in the hippocampus. All applications are limited to non-human research use. |
| Molecular Formula |
C6H9CL2NS
|
|---|---|
| Molecular Weight |
198.113358259201
|
| Exact Mass |
295.952
|
| Elemental Analysis |
C, 36.38; H, 4.58; Cl, 35.79; N, 7.07; S, 16.18
|
| CAS # |
6001-74-7
|
| Related CAS # |
1867-58-9 (edisylate);533-45-9;6001-74-7 (HCl);
|
| PubChem CID |
19035073
|
| Appearance |
Light yellow to yellow solid powder
|
| Melting Point |
136 °C
|
| LogP |
2.238
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
2
|
| Rotatable Bond Count |
2
|
| Heavy Atom Count |
10
|
| Complexity |
89.1
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CC1=C(CCCl)SC=N1.Cl
|
| InChi Key |
OFXYKSLKNMTBHK-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C6H8ClNS.ClH/c1-5-6(2-3-7)9-4-8-5;/h4H,2-3H2,1H3;1H
|
| Chemical Name |
5-(2-chloroethyl)-4-methyl-1,3-thiazole;hydrochloride
|
| Synonyms |
Chlormethiazole hydrochloride; 6001-74-7; Clomethiazole hydrochloride; 5-(2-CHLOROETHYL)-4-METHYLTHIAZOLE HYDROCHLORIDE; Somnevrin hydrochloride; Clomethiazole hydrochloride [MI]; 5-(2-chloroethyl)-4-methyl-1,3-thiazole hydrochloride; 5-(2-chloroethyl)-4-methyl-1,3-thiazole;hydrochloride;
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~630.96 mM)
H2O : ~100 mg/mL (~504.77 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (10.50 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 20.8 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: ≥ 2.08 mg/mL (10.50 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (10.50 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 12.5 mg/mL (63.10 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 5.0477 mL | 25.2385 mL | 50.4770 mL | |
| 5 mM | 1.0095 mL | 5.0477 mL | 10.0954 mL | |
| 10 mM | 0.5048 mL | 2.5239 mL | 5.0477 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
