T3DB: Tizanidine

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (4)XML

Targets (4)

Record Information

Version

2.0

Creation Date

2009-07-21 20:27:26 UTC

Update Date

2014-12-24 20:25:52 UTC

Accession Number

T3D2862

Identification

Common Name

Tizanidine

Class

Small Molecule

Description

Tizanidine is a short-acting drug for the management of spasticity. Tizanidine is an agonist at a2-adrenergic receptor sites and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. In animal models, tizanidine has no direct effect on skeletal muscle fibers or the neuromuscular junction, and no major effect on monosynaptic spinal reflexes. The effects of tizanidine are greatest on polysynaptic pathways. The overall effect of these actions is thought to reduce facilitation of spinal motor neurons.

Compound Type

Adrenergic alpha-2 Receptor Agonist
Adrenergic alpha-Agonist
Amide
Amine
Analgesic
Anticonvulsant
Drug
Metabolite
Muscle Relaxant
Muscle Relaxant, Central
Muscle Relaxant, Skeletal
Neuromuscular Agent
Organic Compound
Organochloride
Parasympatholytic
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
5-Chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole
5-chloro-4-(2-imidazolin-4-on-2-ylamino)-2,1,3-benzothiadiazole
Cimbrar
Musant
Myores
Navizan
Relaxkov
Sirdalid
Sirdalud
Sirdalud MR
Sizolan
Spaslax
Telzanine
Ternelin
Tizadin
Tizaflex
Tizalud
Tizan
Tizanidin
Tizanidina
Tizanidinum
Zanaflex
Zanpeak
Zitanid

Chemical Formula

C₉H₈ClN₅S

Average Molecular Mass

253.711 g/mol

Monoisotopic Mass

253.019 g/mol

CAS Registry Number

51322-75-9

IUPAC Name

5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3-benzothiadiazol-4-amine

Traditional Name

tizanidine

SMILES

ClC1=C(NC2=NCCN2)C2=NSN=C2C=C1

InChI Identifier

InChI=1S/C9H8ClN5S/c10-5-1-2-6-8(15-16-14-6)7(5)13-9-11-3-4-12-9/h1-2H,3-4H2,(H2,11,12,13)

InChI Key

InChIKey=XFYDIVBRZNQMJC-UHFFFAOYSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as benzothiadiazoles. These are heterocyclic aromatic compounds containing a benzene ring fused to a thiadiazole ring. Thiadiazole is a five-membered aromatic heterocycle made up of one sulfur atom and two nitrogen atoms.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Benzothiadiazoles

Sub Class

Not Available

Direct Parent

Benzothiadiazoles

Alternative Parents

Substituents

2,1,3-benzothiadiazole
Aryl chloride
Aryl halide
Benzenoid
Azole
Heteroaromatic compound
2-imidazoline
Thiadiazole
Guanidine
Propargyl-type 1,3-dipolar organic compound
Organic 1,3-dipolar compound
Azacycle
Carboximidamide
Organonitrogen compound
Organochloride
Organohalogen compound
Hydrocarbon derivative
Organopnictogen compound
Organic nitrogen compound
Aromatic heteropolycyclic compound

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

imidazoles (CHEBI:63629 )
benzothiadiazole (CHEBI:63629 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Biological Roles

alpha-adrenergic agonist

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	Not Available
Boiling Point	Not Available
Solubility	1.33e-01 g/L
LogP	1.4

Predicted Properties

Property	Value	Source
Water Solubility	0.13 g/L	ALOGPS
logP	1.6	ALOGPS
logP	2.02	ChemAxon
logS	-3.3	ALOGPS
pKa (Strongest Basic)	7.49	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	62.2 Å²	ChemAxon
Rotatable Bond Count	1	ChemAxon
Refractivity	64.77 m³·mol⁻¹	ChemAxon
Polarizability	23.97 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0a4i-3960000000-3aca4c577af73cfa3997	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0udi-0090000000-03af7132e7796b671fd2	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0udi-2090000000-6ed6a84b177d1e4425ad	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-014i-9020000000-a1d6e32b00fde6ba39d4	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0udi-0090000000-9ebe0248119b57c01175	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0udi-1390000000-5ba6bc72d04cb138d433	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0a4i-2590000000-0e6b317aeab569aa3c97	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0udi-0090000000-81fa3242a4171a3e23e8	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0udi-0090000000-81fa3242a4171a3e23e8	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-000l-0930000000-89d08fc212d90d4e75ee	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0udi-0090000000-809deeeabd14377046e0	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-001i-9000000000-c2fa753da65a4bac80a1	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-001i-9000000000-a9ed1a171086d3aff472	2021-10-11	View Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-0udi-5490000000-5ee0610f321160b63c82	2014-09-20	View Spectrum

Toxicity Profile

Route of Exposure

Oral

Mechanism of Toxicity

Tizanidine reduces spasticity by increasing presynaptic inhibition of motor neurons through agonist action at a2-adrenergic receptor sites.

Metabolism

Route of Elimination: Approximately 95% of an administered dose is metabolized. Half Life: 2.5 hours

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

For the management of increased muscle tone associated with spasticity

Minimum Risk Level

Not Available

Health Effects

May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease.

Symptoms

Not Available

Treatment

Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Due to the similar mechanism of action, symptoms and management of tizanidine overdose are similar to those following clonidine overdose. (2)

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

63629

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Tizanidine

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Tizanidine

References

Synthesis Reference

Pavel Hradil, Lubomir Kvapil, Martin Grepl, Jan Novotny, “METHOD FOR THE PREPARATION OF TIZANIDINE HYDROCHLORIDE.” U.S. Patent US20110263863, issued October 27, 2011.

MSDS

T3D2862.pdf

General References

Drugs.com [Link]
RxList: The Internet Drug Index (2009). [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. Nischarin

General Function:: Phosphatidylinositol binding
Specific Function:: Acts either as the functional imidazoline-1 receptor (I1R) candidate or as a membrane-associated mediator of the I1R signaling. Binds numerous imidazoline ligands that induces initiation of cell-signaling cascades triggering to cell survival, growth and migration. Its activation by the agonist rilmenidine induces an increase in phosphorylation of mitogen-activated protein kinases MAPK1 and MAPK3 in rostral ventrolateral medulla (RVLM) neurons that exhibited rilmenidine-evoked hypotension (By similarity). Blocking its activation with efaroxan abolished rilmenidine-induced mitogen-activated protein kinase phosphorylation in RVLM neurons (By similarity). Acts as a modulator of Rac-regulated signal transduction pathways (By similarity). Suppresses Rac1-stimulated cell migration by interacting with PAK1 and inhibiting its kinase activity (By similarity). Also blocks Pak-independent Rac signaling by interacting with RAC1 and inhibiting Rac1-stimulated NF-kB response element and cyclin D1 promoter activation (By similarity). Inhibits also LIMK1 kinase activity by reducing LIMK1 'Tyr-508' phosphorylation (By similarity). Inhibits Rac-induced cell migration and invasion in breast and colon epithelial cells (By similarity). Inhibits lamellipodia formation, when overexpressed (By similarity). Plays a role in protection against apoptosis. Involved in association with IRS4 in the enhancement of insulin activation of MAPK1 and MAPK3. When overexpressed, induces a redistribution of cell surface ITGA5 integrin to intracellular endosomal structures.
Gene Name:: NISCH
Uniprot ID:: Q9Y2I1
Molecular Weight:: 166627.105 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.028 uM	Not Available	BindingDB 50240671

References

Rolon PA: Myxoglobulosis of the appendix. Int Surg. 1977 Jun-Jul;62(6-7):355-6. [893017 ]
Nikolic K, Filipic S, Agbaba D: QSAR study of imidazoline antihypertensive drugs. Bioorg Med Chem. 2008 Aug 1;16(15):7134-40. doi: 10.1016/j.bmc.2008.06.051. Epub 2008 Jun 28. [18621536 ]

Target Details

2. Alpha-2A adrenergic receptor

General Function:: Thioesterase binding
Specific Function:: Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol.
Gene Name:: ADRA2A
Uniprot ID:: P08913
Molecular Weight:: 48956.275 Da

References

Piletz JE, Zhu H, Chikkala DN: Comparison of ligand binding affinities at human I1-imidazoline binding sites and the high affinity state of alpha-2 adrenoceptor subtypes. J Pharmacol Exp Ther. 1996 Nov;279(2):694-702. [8930173 ]

Target Details

3. Alpha-2B adrenergic receptor

General Function:: Epinephrine binding
Specific Function:: Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is clonidine > norepinephrine > epinephrine = oxymetazoline > dopamine > p-tyramine = phenylephrine > serotonin > p-synephrine / p-octopamine. For antagonists, the rank order is yohimbine > chlorpromazine > phentolamine > mianserine > spiperone > prazosin > alprenolol > propanolol > pindolol.
Gene Name:: ADRA2B
Uniprot ID:: P18089
Molecular Weight:: 49565.8 Da

References

Piletz JE, Zhu H, Chikkala DN: Comparison of ligand binding affinities at human I1-imidazoline binding sites and the high affinity state of alpha-2 adrenoceptor subtypes. J Pharmacol Exp Ther. 1996 Nov;279(2):694-702. [8930173 ]

Target Details

4. Alpha-2C adrenergic receptor

General Function:: Protein homodimerization activity
Specific Function:: Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins.
Gene Name:: ADRA2C
Uniprot ID:: P18825
Molecular Weight:: 49521.585 Da

References

Piletz JE, Zhu H, Chikkala DN: Comparison of ligand binding affinities at human I1-imidazoline binding sites and the high affinity state of alpha-2 adrenoceptor subtypes. J Pharmacol Exp Ther. 1996 Nov;279(2):694-702. [8930173 ]

Tizanidine (T3D2862)

Structure for T3D2862: Tizanidine

Targets

Binding/Activity Constants

References

References

References

References