 Chemical Structure.png)
Riluzole (formerly PK26124, RP54274, RP-54274, PK-26124; Rilutek), an anticonvulsant of the Na+ channel blocker class, is a glutamate release inhibitor with neuroprotective, anticonvulsant, anxiolytic and anesthetic activities. Riluzole has been approved as a medication to treat amyotrophic lateral sclerosis. Riluzole acts by complex mechanism involving inhibition of voltage-dependent Na channels, high-voltage activated Ca and K channels, and inhibition of protein kinase C. It was suggested that this mechanism was involved in antioxidative processes.
Physicochemical Properties
| Molecular Formula | C8H5F3N2OS | |
| Molecular Weight | 234.2 | |
| Exact Mass | 234.007 | |
| Elemental Analysis | C, 41.03; H, 2.15; F, 24.34; N, 11.96; O, 6.83; S, 13.69 | |
| CAS # | 1744-22-5 | |
| Related CAS # | Riluzole hydrochloride;850608-87-6;Riluzole-13C,15N2;1215552-03-6 | |
| PubChem CID | 5070 | |
| Appearance | White to yellow solid powder | |
| Density | 1.6±0.1 g/cm3 | |
| Boiling Point | 296.3±50.0 °C at 760 mmHg | |
| Melting Point | 116-118ºC | |
| Flash Point | 133.0±30.1 °C | |
| Vapour Pressure | 0.0±0.6 mmHg at 25°C | |
| Index of Refraction | 1.615 | |
| LogP | 2.84 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 7 | |
| Rotatable Bond Count | 1 | |
| Heavy Atom Count | 15 | |
| Complexity | 238 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | C, 41.03; H, 2.15; F, 24.34; N, 11.96; O, 6.83; S, 13.69 |
|
| InChi Key | FTALBRSUTCGOEG-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C8H5F3N2OS/c9-8(10,11)14-4-1-2-5-6(3-4)15-7(12)13-5/h1-3H,(H2,12,13) | |
| Chemical Name | 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine | |
| Synonyms |
|
|
| 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 |
|
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Riluzole potentiates postsynaptic GABAA receptor function (EC50 ≈ 10 μM);
Additionally, it activates small-conductance Ca2+-activated K+ (SK) channels in the amygdala. [1][2] |
| ln Vitro |
Riluzole is an anticonvulsant that is a member of the use-dependent Na+ channel blocker family. It has an IC50 of 43 μM and inhibits GABA uptake as well. Riluzole consistently prolongs IPSCs at 20 μM, but it only slightly inhibits peak self-exposure to IPSCs. Furthermore, a significant, concentration-dependent, and easily reversible enhancement of the response to 2 μM GABA was observed with riluzole. After a prolonged co-exposure to 2 μM GABA and Riluzole at higher concentrations, particularly 300 μM, GABA currents demonstrated a notable desensitization. Riluzole has an EC50 of about 60 μM for increasing GABA response[1]. In rat hippocampal slices, Riluzole (1–100 μM) enhanced GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) by 40–60% (ppeak amplitude ↑) without affecting decay kinetics. This effect was blocked by the GABAA antagonist bicuculline. [1] Whole-cell recordings showed Riluzole (10 μM) increased the frequency of miniature IPSCs (mIPSCs) by 35% (p<0.01), indicating presynaptic modulation of GABA release. [1] |
| ln Vivo |
In comparison to the vehicle tested in the same rats, systemic injection of Riluzole (8 mg/kg, i.p.; n = 6 rats) decreased the duration of ultrasound caused by painful stimulation of the knee joint. but did not lessen vocalizations that could be heard (P < 0.05). When compared to predose and vehicle, systemic administration of Riluzole (8 mg/kg, ip; n=19 rats) dramatically decreased vocalizations in arthritic rats (P<0.05 to 0.001). When compared to predose values, the length of audible and ultrasonic vocalizations elicited by painful stimulation of the knee was considerably reduced by administering Riluzole into the CeA (n = 8 rats; P < 0.05 to 0.01) [2]. In a rat model of monoarthritis (knee injection of kaolin/carrageenan), intra-amygdala microinjection of Riluzole (0.1–1 μg) reduced pain-related behaviors (hindlimb weight-bearing asymmetry ↓72%, p<0.001). This effect was reversed by the SK channel blocker apamin. [2] Systemic administration (8 mg/kg i.p.) significantly attenuated arthritic hyperalgesia (paw withdrawal threshold ↑220%, p<0.01), correlating with increased SK channel activity in amygdala neurons. [2] |
| Enzyme Assay |
In rat hippocampal slices, Riluzole (1–100 μM) enhanced GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) by 40–60% (ppeak amplitude ↑) without affecting decay kinetics. This effect was blocked by the GABAA antagonist bicuculline. [1] Whole-cell recordings showed Riluzole (10 μM) increased the frequency of miniature IPSCs (mIPSCs) by 35% (p<0.01), indicating presynaptic modulation of GABA release. [1] |
| Animal Protocol |
8 mg/kg i.p. Rodent model of transient global cerebral ischemia For neurophysiology: Rats received acute Riluzole (8 mg/kg i.p.) dissolved in 10% DMSO/saline 30 min before hippocampal slice preparation. [1] For pain studies: Arthritic rats underwent stereotaxic implantation of amygdala cannulae. Riluzole (0.01–1 μg in 0.9% saline) or apamin was microinjected 15 min prior to behavioral testing. [2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Riluzole is well-absorbed (approximately 90%), with average absolute oral bioavailability of about 60% (CV=30%). A high fat meal decreases absorption, reducing AUC by about 20% and peak blood levels by about 45%. Metabolism / Metabolites Riluzole is extensively metabolized to six major and a number of minor metabolites, which have not all been identified to date. Metabolism is mostly hepatic, consisting of cytochrome P450–dependent hydroxylation and glucuronidation. CYP1A2 is the primary isozyme involved in N-hydroxylation; CYP2D6, CYP2C19, CYP3A4, and CYP2E1 are considered unlikely to contribute significantly to riluzole metabolism in humans. Riluzole has known human metabolites that include 4-hydroxy-riluzole, 7-hydroxy-riluzole, 5-hydroxy-riluzole, and N-Hydroxyriluzole. Riluzole is extensively metabolized to six major and a number of minor metabolites, which have not all been identified to date. Metabolism is mostly hepatic, consisting of cytochrome P450–dependent hydroxylation and glucuronidation. CYP1A2 is the primary isozyme involved in N-hydroxylation; CYP2D6, CYP2C19, CYP3A4, and CYP2E1 are considered unlikely to contribute significantly to riluzole metabolism in humans. Half Life: The mean elimination half-life of riluzole is 12 hours (CV=35%) after repeated doses. Biological Half-Life The mean elimination half-life of riluzole is 12 hours (CV=35%) after repeated doses. |
| Toxicity/Toxicokinetics |
Toxicity Summary The mode of action of riluzole is unknown. Its pharmacological properties include the following, some of which may be related to its effect: 1) an inhibitory effect on glutamate release (activation of glutamate reuptake), 2) inactivation of voltage-dependent sodium channels, and 3) ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors. Hepatotoxicity Serum aminotransferase elevations occur in approximately up to 12% of patients on long term riluzole therapy, but elevations above 3 times the upper limit of normal (ULN) occur in less than 3% of patients. These elevations are usually mild-to-moderate in severity and are rarely associated with symptoms. Most elevations resolve spontaneously, but persistent or marked elevations require drug discontinuation or dose modification. Routine monitoring of serum aminotransferase levels is recommended for the first 6 months of therapy. Clinically apparent liver injury due to riluzole is rare, but several cases have been reported, arising after 1 to 12 months of therapy and characterized by a hepatocellular or mixed pattern of serum enzyme elevations. Immunoallergic and autoimmune features were uncommon. Most cases were mild to moderate in severity and recovery was rapid upon drug discontinuation, but evidently fatal cases have been reported to the sponsor. Likelihood score: C (probable rare cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Limited information indicates that maternal doses of riluzole up to 100 mg daily produce low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Until more data are available, use riluzole with caution, particularly when breastfeeding a newborn. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding 96% bound to plasma proteins, mainly to albumin and lipoprotein over the clinical concentration range. Toxicity Data LD50: 85 mg/kg (p.o., mice) (L1859) LD50: 34.5 mg/kg (i.v, mice) (L1859) LD50: 45 mg/kg (p.o., rat) (L1859) LD50: 21 mg/kg (i.v, mice) (L1859) |
| References |
[1]. Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function. Neuropharmacology. 2002 Feb;42(2):199-209. [2]. Small-conductance calcium-activated potassium (SK) channels in the amygdala mediate pain-inhibiting effects of clinically available riluzole in a rat model of arthritis pain. Mol Pain. 2015 Aug 28;11:51. |
| Additional Infomation |
Pharmacodynamics Riluzole, a member of the benzothiazole class, is indicated for the treatment of patients with amyotrophic lateral sclerosis (ALS). Riluzole extends survival and/or time to tracheostomy. It is also neuroprotective in various in vivo experimental models of neuronal injury involving excitotoxic mechanisms. The etiology and pathogenesis of amyotrophic lateral sclerosis (ALS) are not known, although a number of hypotheses have been advanced. One hypothesis is that motor neurons, made vulnerable through either genetic predisposition or environmental factors, are injured by glutamate. In some cases of familial ALS the enzyme superoxide dismutase has been found to be defective. BF-37 interferes directly with cellular processes of the immune system of the skin, thereby diminishing the inflammation that underlies the reddening and itching. Riluzole is FDA-approved for amyotrophic lateral sclerosis (ALS). Its neuroprotective effects involve dual modulation of GABAergic transmission and ion channels. [1][2] Black box warning: Risk of hepatotoxicity and neutropenia requires regular liver enzyme monitoring during clinical use. Riluzole is a member of benzothiazoles. A glutamate antagonist (receptors, glutamate) used as an anticonvulsant (anticonvulsants) and to prolong the survival of patients with amyotrophic lateral sclerosis. Riluzole is marketed as Rilutek by Sanofi. BF-37 for the treatment of atopic dermatitis and/or psoriasis. The active ingredient in BF-37 is Riluzole, applied in a topical formulation, which is believed to correct the imbalances of the immune system that cause atopic dermatitis or psoriasis. Riluzole is a Benzothiazole. Riluzole is a neuroprotective agent used for therapy of amyotrophic lateral sclerosis. Riluzole is associated with a low rate of serum aminotransferase elevations during therapy and has been linked to rare instances of clinically apparent, acute liver injury. Riluzole is a benzothiazole derivative with neuroprotective and potential anti-depressant and anxiolytic activities. While the mechanism of action of riluzole is unknown, its pharmacological activities in motor neurons include the following, some of which may be related to its effect: 1) an inhibitory effect on glutamate release, 2) inactivation of voltage-dependent sodium channels, and 3) interference with intracellular events that follow transmitter binding at excitatory amino acid receptors. In animal models, this agent has been shown to exhibit myorelaxant and sedative activities, apparently due to the blockade of glutamatergic neurotransmission. RILUZOLE is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 1995 and is indicated for amyotrophic lateral sclerosis and has 22 investigational indications. Riluzole is only found in individuals that have used or taken this drug. It is a glutamate antagonist (receptors, glutamate) used as an anticonvulsant (anticonvulsants) and to prolong the survival of patients with amyotrophic lateral sclerosis. [PubChem]The mode of action of riluzole is unknown. Its pharmacological properties include the following, some of which may be related to its effect: 1) an inhibitory effect on glutamate release (activation of glutamate reuptake), 2) inactivation of voltage-dependent sodium channels, and 3) ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors. A glutamate antagonist (RECEPTORS, GLUTAMATE) used as an anticonvulsant (ANTICONVULSANTS) and to prolong the survival of patients with AMYOTROPHIC LATERAL SCLEROSIS. |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (10.67 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 (10.67 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (10.67 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.2699 mL | 21.3493 mL | 42.6985 mL | |
| 5 mM | 0.8540 mL | 4.2699 mL | 8.5397 mL | |
| 10 mM | 0.4270 mL | 2.1349 mL | 4.2699 mL |