Chlormezanone targets GABAA receptors, acting as a positive modulator at the benzodiazepine binding site. It enhances GABA-mediated inhibitory neurotransmission in the central nervous system, resulting in muscle relaxation and anxiolytic effects. It is a substrate of the GABA receptor.

In vitro, chlormezanone binds to the benzodiazepine site of GABAA receptors with moderate affinity. It potentiates GABA-induced chloride currents in electrophysiological studies using recombinant GABAA receptors expressed in oocytes or mammalian cells. Specific IC₅₀/EC₅₀ values are not extensively documented in the available literature.

Comparative outcomes achieved with a dosage of chlormezazone that inhibited the contralateral extensor muscles by more than 80% [1].
In vivo, chlormezanone exhibits central muscle relaxant and anxiolytic effects in animal models. It has been shown to reduce muscle tone and anxiety-like behaviors in rodents. It was clinically used for the management of anxiety and muscle spasm before its discontinuation.

Receptor binding assays are performed using membrane preparations from rat brain or cells expressing recombinant GABAA receptors. Radioligand displacement assays use [³H]-flunitrazepam or [³H]-muscimol to assess binding to the benzodiazepine or GABA site. Chlormezanone is tested at various concentrations, and IC₅₀/Ki values are calculated. Electrophysiological studies use two-electrode voltage clamp in Xenopus oocytes.

In vitro cellular assays use cell lines expressing GABAA receptors (e.g., HEK293, CHO cells transfected with receptor subunits). Cells are treated with chlormezanone and GABA, and chloride influx is measured using fluorescent indicators or patch-clamp electrophysiology. Potentiation of GABA responses is assessed by comparing currents with and without chlormezanone.

In vivo efficacy is evaluated in rodent models of anxiety (e.g., elevated plus maze, light-dark box, open field) and muscle spasm (e.g., spinal cord transection, chemically-induced spasticity). Chlormezanone is administered orally or intraperitoneally. Anxiolytic and muscle relaxant effects are quantified by behavioral parameters.

Absorption, Distribution and Excretion
Rapidly absorbed via the gastrointestinal tract…onset of action within 15 to 30 minutes…duration of action 4 to 6 hours…free drug and/or 4-chlorohippuric acid/excreted in urine/human, orally/…higher concentrations in the kidneys, liver, muscles, heart, and body fat, lower concentrations in the lungs and plasma/rat, orally/. Following oral administration of (14)C-chloromezafone, approximately 74% of the dose in rats is excreted in urine within 24 hours, and approximately 21% in mice within 2 hours. The amount of radioactive material excreted in rat bile is approximately 10% of the dose. Metabolism/Metabolites Chloromezafone…excreted unchanged in human urine and dog bile. 4-chlorohippuric acid is the main metabolite in human urine, its formation involving non-enzymatic hydrolysis, followed by oxidation and conjugation of the hydrolysis product 4-chlorobenzaldehyde.
(14) The metabolites of C-chloromethazine in the urine of rats and mice are p-chlorobenzoic acid, p-chlorohippuric acid, N-methyl-p-chlorobenzoamide, 2-[N-methyl-N-(p-chlorobenzoyl)]carbamoylethylsulfonic acid, 3-sulfopropionic acid and glucuronide of p-chlorobenzoic acid.
Chlormezanone is rapidly absorbed after oral administration, with peak plasma concentrations reached within 1-2 hours. It is metabolized in the liver and excreted primarily in urine. The half-life is approximately 4-6 hours. Specific pharmacokinetic parameters are less extensively documented due to its discontinuation.

Toxicity Summary
Clomezadone binds to central benzodiazepine receptors, which in turn undergo allosteric interactions with GABA receptors. This enhances the effects of the inhibitory neurotransmitter GABA, increases inhibition of the ascending reticular activating system, and blocks cortical and limbic excitation following reticular pathway stimulation. Interactions Clomezadone may reduce patient tolerance to alcohol… and may have additive effects with clomezadone and/or central nervous system depressants such as alcohol, phenothiazines, barbiturates, narcotics, other psychotropic drugs, and monoamine oxidase inhibitors.
The most significant toxicity of chlormezanone is rare but serious cutaneous reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), which led to its worldwide withdrawal in 1996. Other adverse effects include drowsiness, dizziness, and gastrointestinal disturbances. It is contraindicated in patients with porphyria.

[1]. EFFECTS OF NEW s-TRIAZOLOBENZODIAZEPINE (D-4OTA) AND OTHER CENTRAL MUSCLE RELAXANTS ON SPINAL AND SUPRASPINAL REFLEXES IN CATS. Japan. J. Pharmacol, 23, 83-96 (1973).

Chlormethazine is a 1,3-thiazine compound, chemically named 1,3-thiazin-4-one S,S-dioxide, in which the hydrogen at the 2-position is replaced by a 4-chlorophenyl group and the hydrogen on the nitrogen atom is replaced by a methyl group. It is a non-benzodiazepine muscle relaxant, formerly used to treat anxiety and muscle cramps, but its manufacturer discontinued production globally in 1996 due to rare but serious skin reactions. Chlormethazine has anti-anxiety, muscle relaxant, and antipsychotic effects. It is a 1,3-thiazine compound, belonging to the lactam, sulfone class, and monochlorobenzene class. It is a non-benzodiazepine drug, formerly used to treat anxiety. There have been suggestions for its use in treating muscle cramps. Chlormethazine is only present in individuals who have used or taken the drug. It is a non-benzodiazepine drug, formerly used to treat anxiety. Chlormethazine has been recommended for the treatment of muscle cramps. [PubChem]Climezafone binds to central benzodiazepine receptors, which in turn undergo allosteric interactions with GABA receptors. This enhances the effect of the inhibitory neurotransmitter GABA, increases inhibition of the ascending reticular activating system, and blocks cortical and limbic excitation following stimulation of the reticular pathway.
A non-benzodiazepine drug used to treat anxiety. It has been recommended for the treatment of muscle spasms.

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Drug Indications
For the treatment of anxiety and muscle spasms.

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Mechanism of Action
Climezafone binds to central benzodiazepine receptors, which in turn undergo allosteric interactions with GABA receptors. This enhances the effect of the inhibitory neurotransmitter GABA, increases inhibition of the ascending reticular activating system, and blocks cortical and limbic excitation following stimulation of the reticular pathway.
Unless near a lethal dose, nerve conduction, neuromuscular transmission, and muscle excitability are not inhibited. A significant effect is the preferential inhibition of spinal polysynaptic reflexes rather than monosynaptic reflexes. /Central Muscle Relaxants/
In the absence of conclusive research, attributing beneficial effects to their sedative properties seems reasonable. /Central Muscle Relaxants/

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Therapeutic Uses
Anxiety medication; Central muscle relaxants
...Intravenous injection has been shown to be effective in treating acute muscle spasms caused by trauma and inflammation. ...Also helpful for muscle relaxation in certain orthopedic manipulations. ...May temporarily relieve some symptoms of cerebral palsy... /Central Muscle Relaxants/
Many drugs with muscle-relaxing properties produce significant sedative effects at ordinary oral doses. These drugs are particularly widely used in the treatment of muscle tension and pain associated with anxiety states and psychosomatic disorders. /Central Muscle Relaxants/
Muscle relaxants relax skeletal muscles by selectively acting on the central nervous system without causing loss of consciousness. ...All types of extrinsic hypertonia and hyperreflexia...caused by lesions of the spinal cord or supraspinal cord, can be relieved...In addition...it can prevent...convulsants.../central muscle relaxants/
...It is as effective as clozapine in treating mild anxiety. Symptoms of musculoskeletal disorders exacerbated by anxiety and tension may respond to its sedative effect...It appears to have no specific effect on spasms or stiffness associated with organoneurinic disorders.
Drug Warnings

Sometimes metabolites can discolor urine.
Adverse reactions are usually mild and occur relatively infrequently, but in two controlled studies, adverse reactions were more common than with clozapine.
...Some sedative effect is produced at least at the highest clinically used dose. /central muscle relaxants/
Pharmacodynamics
Climezapine is a non-benzodiazepine muscle relaxant. Its manufacturer discontinued production worldwide in 1996 due to its proven ability to cause severe and rare skin reactions (toxic epidermal necrolysis).
Chlormezanone (Trancopal, Rilansyl) was a centrally acting muscle relaxant and anxiolytic marketed in many countries. It was discontinued by its manufacturer in 1996 due to rare but severe cutaneous adverse reactions (toxic epidermal necrolysis). It is no longer clinically available but may be encountered as a research compound or reference standard.

C11H12CLNO3S

273.74

273.022

80-77-3

2717

White to off-white solid powder

1.4±0.1 g/cm3

534.5±50.0 °C at 760 mmHg

114ºC

277.1±30.1 °C

0.0±1.4 mmHg at 25°C

1.580

0.86

0

3

1

17

395

0

WEQAYVWKMWHEJO-UHFFFAOYSA-N

InChI=1S/C11H12ClNO3S/c1-13-10(14)6-7-17(15,16)11(13)8-2-4-9(12)5-3-8/h2-5,11H,6-7H2,1H3

2-(4-chlorophenyl)-3-methyl-1,1-dioxo-1,3-thiazinan-4-one

Trancopal; Chlormethazanone; Chlormezanone

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~365.31 mM)
H2O : ~0.67 mg/mL (~2.45 mM)

Solubility in Formulation 1: ≥ 3.25 mg/mL (11.87 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 32.5 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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.

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Solubility in Formulation 2: ≥ 3.25 mg/mL (11.87 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 32.5 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.

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Solubility in Formulation 3: ≥ 3.25 mg/mL (11.87 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 32.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)