Riluzole (T3D2875)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (5)XML
Targets (5)
Record Information
Version2.0
Creation Date2009-07-21 20:27:32 UTC
Update Date2014-12-24 20:25:52 UTC
Accession NumberT3D2875
Identification
Common NameRiluzole
ClassSmall Molecule
DescriptionRiluzole 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.
Compound Type
  • Amine
  • Anesthetic
  • Anticonvulsant
  • Drug
  • Ether
  • Excitatory Amino Acid Antagonist
  • Metabolite
  • Neuroprotective Agent
  • Organic Compound
  • Organofluoride
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDF3D-SDFPDBSMILESInChI View 3D Structure
Synonyms
Synonym
Fanizan
Laidec
Lizolorol
Lizorolol
Rilustad
Rilutek
Riluzol
Riluzolum
Sclefic
Xie Yi Li
Zolerilis
Chemical FormulaC8H5F3N2OS
Average Molecular Mass234.198 g/mol
Monoisotopic Mass234.007 g/mol
CAS Registry Number1744-22-5
IUPAC Name6-(trifluoromethoxy)-1,3-benzothiazol-2-amine
Traditional Nameriluzole
SMILESFC(F)(F)OC1=CC2=C(NC(=N)S2)C=C1
InChI IdentifierInChI=1S/C8H5F3N2OS/c9-8(10,11)14-4-1-2-5-6(3-4)15-7(12)13-5/h1-3H,(H2,12,13)
InChI KeyInChIKey=FTALBRSUTCGOEG-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as benzothiazoles. These are organic compounds containing a benzene fused to a thiazole ring (a five-membered ring with four carbon atoms, one nitrogen atom and one sulfur atom).
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzothiazoles
Sub ClassNot Available
Direct ParentBenzothiazoles
Alternative Parents
Substituents
  • 1,3-benzothiazole
  • Benzenoid
  • 1,3-thiazol-2-amine
  • Azole
  • Thiazole
  • Heteroaromatic compound
  • Trihalomethane
  • Azacycle
  • Amine
  • Organopnictogen compound
  • Organic oxygen compound
  • Alkyl halide
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Organic nitrogen compound
  • Alkyl fluoride
  • Hydrocarbon derivative
  • Halomethane
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point119°C
Boiling PointNot Available
Solubility3.95e-02 g/L
LogP2.3
Predicted Properties
PropertyValueSource
Water Solubility0.04 g/LALOGPS
logP2.83ALOGPS
logP3.4ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)16.44ChemAxon
pKa (Strongest Basic)4.57ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area48.14 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity44.37 m³·mol⁻¹ChemAxon
Polarizability18.59 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-00li-2940000000-00c484cbc92e6a94bae02017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-000i-2590000000-5a9d0f7cdad7e4f2ec6b2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-000i-0390000000-4bd44ae3d25f047943e82017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-000i-3940000000-1da38288b84e863a64e52017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 35V, Positivesplash10-000i-0590000000-79d300cfd2b43692d9632021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 35V, Negativesplash10-001i-0190000000-63069bec4e00478eb3802021-09-20View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-000i-0190000000-f0b481a2910122ad9bdc2016-06-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-000i-0090000000-d6a855ead1f5f5fe1a372016-06-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-014i-0900000000-b797bc65c275796519492016-06-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-0090000000-4caa5c429c103b56c1512016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-001i-0090000000-78bd33541d87ef6453032016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-03di-0900000000-6f96de4ddfa58b872d2e2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-000i-0090000000-77cd58803ff632c890022021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-000i-0090000000-77cd58803ff632c890022021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4r-0490000000-ab117c07a1f16bb2d5f82021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-0090000000-9f868134c3a763fd526e2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-001i-0090000000-9f868134c3a763fd526e2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4i-9320000000-2312256d22d9ca57d0142021-10-11View Spectrum
Toxicity Profile
Route of ExposureRiluzole 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%.
Mechanism of ToxicityThe 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.
MetabolismRiluzole 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.
Toxicity ValuesLD50: 85 mg/kg (p.o., mice) (8) LD50: 34.5 mg/kg (i.v, mice) (8) LD50: 45 mg/kg (p.o., rat) (8) LD50: 21 mg/kg (i.v, mice) (8)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the treatment of amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease)
Minimum Risk LevelNot Available
Health EffectsMay cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease.
SymptomsSymptoms include such as nausea and fatigue [Wikipedia].
TreatmentTreatment should be supportive and directed toward alleviating symptoms. Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue. (9)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00740
HMDB IDHMDB14878
PubChem Compound ID5070
ChEMBL IDCHEMBL744
ChemSpider ID4892
KEGG IDC07937
UniProt IDNot Available
OMIM ID
ChEBI ID138898
BioCyc IDNot Available
CTD IDNot Available
Stitch IDRiluzole
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkRiluzole
References
Synthesis Reference

Pratap Padi, Madhusudhan Ganta, Satyanarayana Bollikonda, Sridhar Chaganti, Ramulu Akula, Loka Maheshwari Dommati, “PROCESS FOR PREPARING RILUZOLE.” U.S. Patent US20080108827, issued May 08, 2008.

MSDST3D2875.pdf
General References
  1. Song JH, Huang CS, Nagata K, Yeh JZ, Narahashi T: Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels. J Pharmacol Exp Ther. 1997 Aug;282(2):707-14. [9262334 ]
  2. Coric V, Taskiran S, Pittenger C, Wasylink S, Mathalon DH, Valentine G, Saksa J, Wu YT, Gueorguieva R, Sanacora G, Malison RT, Krystal JH: Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. 2005 Sep 1;58(5):424-8. [15993857 ]
  3. van Kan HJ, Groeneveld GJ, Kalmijn S, Spieksma M, van den Berg LH, Guchelaar HJ: Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis. Br J Clin Pharmacol. 2005 Mar;59(3):310-3. [15752377 ]
  4. Zarate CA Jr, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK: An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004 Jan;161(1):171-4. [14702270 ]
  5. Mathew SJ, Manji HK, Charney DS: Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92. doi: 10.1038/sj.npp.1301652. Epub 2008 Jan 2. [18172433 ]
  6. Lamanauskas N, Nistri A: Riluzole blocks persistent Na+ and Ca2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. Eur J Neurosci. 2008 May;27(10):2501-14. doi: 10.1111/j.1460-9568.2008.06211.x. Epub 2008 Apr 26. [18445055 ]
  7. Drugs.com [Link]
  8. Sanofi Aventis Fact Sheet for Rilutek(Riluzole) [Link]
  9. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated GenesNot Available

Targets

Target Details
1. Cystine/glutamate transporter
General Function:
Cystine:glutamate antiporter activity
Specific Function:
Sodium-independent, high-affinity exchange of anionic amino acids with high specificity for anionic form of cystine and glutamate.
Gene Name:
SLC7A11
Uniprot ID:
Q9UPY5
Molecular Weight:
55422.44 Da
References
  1. Wokke J: Riluzole. Lancet. 1996 Sep 21;348(9030):795-9. [8813989 ]
  2. Azbill RD, Mu X, Springer JE: Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Res. 2000 Jul 21;871(2):175-80. [10899284 ]
  3. Dunlop J, Beal McIlvain H, She Y, Howland DS: Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis. J Neurosci. 2003 Mar 1;23(5):1688-96. [12629173 ]
  4. Gosselin RD, O'Connor RM, Tramullas M, Julio-Pieper M, Dinan TG, Cryan JF: Riluzole normalizes early-life stress-induced visceral hypersensitivity in rats: role of spinal glutamate reuptake mechanisms. Gastroenterology. 2010 Jun;138(7):2418-25. doi: 10.1053/j.gastro.2010.03.003. Epub 2010 Mar 10. [20226190 ]
  5. Hayashida K, Parker RA, Eisenach JC: Activation of glutamate transporters in the locus coeruleus paradoxically activates descending inhibition in rats. Brain Res. 2010 Mar 4;1317:80-6. doi: 10.1016/j.brainres.2009.12.086. Epub 2010 Jan 6. [20059984 ]
Target Details
2. Glutamate receptor ionotropic, NMDA 3A
General Function:
Protein phosphatase 2a binding
Specific Function:
NMDA receptor subtype of glutamate-gated ion channels with reduced single-channel conductance, low calcium permeability and low voltage-dependent sensitivity to magnesium. Mediated by glycine. May play a role in the development of dendritic spines. May play a role in PPP2CB-NMDAR mediated signaling mechanism (By similarity).
Gene Name:
GRIN3A
Uniprot ID:
Q8TCU5
Molecular Weight:
125464.07 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
Target Details
3. Sodium channel protein type 5 subunit alpha
General Function:
Voltage-gated sodium channel activity involved in sa node cell action potential
Specific Function:
This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels.
Gene Name:
SCN5A
Uniprot ID:
Q14524
Molecular Weight:
226937.475 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
Target Details
4. Dihydrofolate reductase
General Function:
Nadph binding
Specific Function:
Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.
Gene Name:
DHFR
Uniprot ID:
P00374
Molecular Weight:
21452.61 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50312 uMNot AvailableBindingDB 30705
References
  1. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
Target Details
5. Sodium channel protein type 2 subunit alpha
General Function:
Voltage-gated sodium channel activity
Specific Function:
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient.
Gene Name:
SCN2A
Uniprot ID:
Q99250
Molecular Weight:
227972.64 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC502.2 uMNot AvailableBindingDB 30705
References
  1. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]