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| Targets |
(S)-Carisbamate targets multiple molecular entities involved in neuronal excitability. It inhibits voltage-gated sodium channels (Nav), which are responsible for the generation and propagation of action potentials in neurons. By binding to specific amino acid residues in these channels, carisbamate inhibits their activity, leading to a reduction in neuronal excitability. Carisbamate also interacts with HCN channels (hyperpolarization-activated cyclic nucleotide-gated channels). The compound is a non-competitive antagonist of the ryanodine receptor, which is involved in calcium release from the endoplasmic reticulum. Carisbamate inhibits glutamate transmission in the granule cells of the dentate gyrus. This multi-target mechanism contributes to its anticonvulsant and neuroprotective effects.
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| ln Vitro |
In the SRED model of hippocampus cells, carisbamate (200 µM; 12 hours) exhibits anti-epileptic properties [1]. Long-lasting effects on hippocampal neurons are demonstrated by carisbamate (200 µM; 24 hours), which are not correlated with antiepileptic effects in vitro [1]. In the few neurons that still occasionally experience epileptiform events, carisbamate not only inhibits the development and expression of SRED in the majority of neurons, but it also shortens the duration and frequency of seizures [1]. Hippocampal cells with injury resembling status epilepticus can benefit from neuroprotective actions of carisbamate (200 µM) [1].
In vitro, carisbamate inhibits repetitive firing of action potentials and voltage-gated sodium channels (Nav) in rat hippocampal neurons. The compound has no effect on voltage-gated potassium (Kv) channels, indicating selectivity for sodium channels. Carisbamate prevents the development and generation of epileptiform discharges and has neuroprotective effects after epileptiform injury in vitro. The compound blocks neuronal death induced by kainic acid, a model of excitotoxicity. These in vitro findings support the anticonvulsant and neuroprotective activity of carisbamate. |
| ln Vivo |
Carisbamate (10, 30, 60 mg/kg; intraperitoneal injection; single dosage) dose-dependently lowers the expression of spike-wave discharges (SWD) in a rat model of absence seizures [2]. Carisbamate (20, 30 mg/kg; i.p.; single dosage) did not elicit galloping or tonic seizures in any of the rats examined [2].
In vivo, carisbamate (10-60 mg/kg) dose-dependently reduces spike and wave discharges in the frontoparietal cortex in a rat model of absence seizures. Carisbamate (10 mg/kg) increases latency to the first running episode in the Wistar audiogenic sensitive rat model of convulsive seizures. The compound reduces motor seizure frequency in a rat model of spontaneous seizures in a dose-dependent manner. Carisbamate acutely suppresses spasms in a rat model of symptomatic infantile spasms. Carisbamate has been shown to be effective against seizures induced by pentylenetetrazol and electroshock in rats. These in vivo studies demonstrate the broad anticonvulsant activity of carisbamate across multiple seizure models. |
| Enzyme Assay |
Carisbamate's interaction with voltage-gated sodium channels is assessed using electrophysiological techniques. Patch-clamp recordings from rat hippocampal neurons or heterologous expression systems are used to measure the effects of carisbamate on sodium channel currents. Voltage-clamp protocols are employed to assess the state-dependent inhibition of sodium channels. Radioligand binding assays using [3H]-labeled ligands may also be used to assess binding affinity to sodium channels. These assays provide mechanistic insights into the anticonvulsant activity of carisbamate.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: Hippocampal cells (from postnatal day 2 Sprague-Dawley rats; Spontaneous Recurrent Epileptiform Discharges (SRED) model) Tested Concentrations: 200 µM Incubation Duration: 12 hrs (hours) Experimental Results: Response to SRED The acute inhibition rate is greater than 95% of neurons showing anti-epileptic effects in vitro. Cell viability assay[1] Cell Types: Hippocampal cells (SREDs model) Tested Concentrations: 200 µM Incubation Duration: 24 hrs (hours) Experimental Results: Display cells evaluated the day after treatment still had no in vitro epileptic activity and no SREDs were formed. Carisbamate is tested on cultured rat hippocampal neurons or other neuronal cell lines. Neurons are treated with varying concentrations of carisbamate; action potential firing is assessed by patch-clamp electrophysiology or multi-electrode array recordings; neuronal viability is assessed by MTT or LDH assays following exposure to excitotoxic insults (e.g., kainic acid, glutamate). Epileptiform activity is induced by pharmacological manipulation (e.g., 4-AP, picrotoxin) and the ability of carisbamate to suppress this activity is assessed. These cell-based assays provide evidence for the anticonvulsant and neuroprotective effects of carisbamate. |
| Animal Protocol |
Animal/Disease Models: Male genetic absence epilepsy rat (absence seizure model) [2].
Doses: 10, 30, 60 mg/kg Route of Administration: intraperitoneal (ip) injection; single. Experimental Results: SWD was completely inhibited after 120 min at 60 mg/kg, and SWD duration returned to control levels after 100 min at 30 mg/kg. Animal/Disease Models: Male Wistar hearing-sensitive rat (convulsive seizure model) [2]. Doses: 10, 20, 30 mg/kg Route of Administration: intraperitoneal (ip) injection; single. Experimental Results: At doses of 20 and 30 mg/kg, none of the rats tested developed galloping or tonic seizures. At a dose of 10 mg/kg, 6 of the 8 rats studied still developed tonic seizure latency, which increased by 327%. Carisbamate is evaluated in various animal models of epilepsy and seizures. Models include pentylenetetrazol-induced seizures, maximal electroshock seizures, absence seizure models (genetic or pharmacologically induced), audiogenic seizure models, and kainic acid-induced status epilepticus. Carisbamate is administered orally or intraperitoneally at doses ranging from 10-60 mg/kg. Seizure parameters (latency, duration, severity, incidence) are recorded; spike-wave discharge frequency is measured by EEG. Neuroprotection is assessed by histological examination of brain tissue following excitotoxic injury. These in vivo studies are critical for demonstrating the anticonvulsant activity of carisbamate. |
| ADME/Pharmacokinetics |
Pharmacokinetic studies indicate that carisbamate is orally bioavailable. The compound is well-absorbed following oral administration and distributes to the brain, consistent with its central nervous system activity. Carisbamate is metabolized in the liver and excreted in urine and feces. Specific pharmacokinetic parameters such as half-life, Cmax, Tmax, and bioavailability have been characterized in preclinical and clinical studies. The compound's pharmacokinetic properties support oral dosing in clinical settings.
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| Toxicity/Toxicokinetics |
Carisbamate has been evaluated in clinical trials for epilepsy. The compound has been shown to reduce seizure frequency in patients with refractory epilepsy. Common adverse effects associated with carisbamate include dizziness, somnolence, headache, and fatigue. Serious adverse events are uncommon. The safety profile of carisbamate is consistent with other anticonvulsant agents. Carisbamate is generally well-tolerated at therapeutic doses.
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| References | |
| Additional Infomation |
Carribacyl is an organochlorine compound. Carribacyl has been studied in relation to alcohol abuse, drug abuse, and alcohol dependence. Indications: Infantile spasms (Wester syndrome), Lennox-Gastaut syndrome, focal (partial) symptomatic epilepsy and epilepsy syndromes with simple partial seizures, neonatal seizures, other childhood epilepsy syndromes such as Dravet syndrome, myoclonic atonic syndrome, persistent sharp wave epilepsy during sleep, idiopathic partial epilepsy, absence epilepsy.
(S)-Carisbamate is the S-enantiomer of carisbamate, a neuromodulator with anticonvulsant and neuroprotective properties. The compound inhibits voltage-gated sodium channels and HCN channels, and is a non-competitive antagonist of the ryanodine receptor. Carisbamate has been evaluated in clinical trials for epilepsy and has shown efficacy in reducing seizure frequency in patients with refractory epilepsy. The compound is not currently approved as a therapeutic agent in major markets but continues to be studied for its potential in epilepsy and other neurological disorders. (S)-Carisbamate is used in research for studying the mechanisms of epilepsy and seizure disorders. |
| Molecular Formula |
C9H10CLNO3
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|---|---|
| Molecular Weight |
215.63400
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| Exact Mass |
215.035
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| CAS # |
194085-75-1
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| Related CAS # |
Carisbamate-d4;1292841-50-9;(R)-Carisbamate-d4;1287128-99-7;(Rac)-Carisbamate-d4;1329808-36-7
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| PubChem CID |
6918474
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| Appearance |
White to off-white solid powder
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| LogP |
2.169
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
14
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| Complexity |
201
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1=CC=C(C(=C1)[C@@H](COC(=O)N)O)Cl
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| InChi Key |
OLBWFRRUHYQABZ-MRVPVSSYSA-N
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| InChi Code |
InChI=1S/C9H10ClNO3/c10-7-4-2-1-3-6(7)8(12)5-14-9(11)13/h1-4,8,12H,5H2,(H2,11,13)/t8-/m1/s1
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| Chemical Name |
[(2S)-2-(2-chlorophenyl)-2-hydroxyethyl] carbamate
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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 : ≥ 100 mg/mL (~463.76 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (11.59 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 25.0 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: ≥ 2.5 mg/mL (11.59 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 25.0 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: ≥ 2.5 mg/mL (11.59 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.6376 mL | 23.1879 mL | 46.3757 mL | |
| 5 mM | 0.9275 mL | 4.6376 mL | 9.2751 mL | |
| 10 mM | 0.4638 mL | 2.3188 mL | 4.6376 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.
Study for Safety and Effectiveness of RWJ-333369 (Carsibamate) for the Treatment of Diabetic Peripheral Neuropathy (DPN).
CTID: NCT00501202
Phase: Phase 2 Status: Completed
Date: 2018-05-01
Products are for research use only; We do not sell to patients
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