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targets (4) enzymes (1)
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Identification
Name Tizanidine
Accession Number DB00697 (APRD00128)
Type small molecule
Groups approved
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.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Tizanidina [INN-Spanish]
  • Tizanidine Hcl
  • Tizanidinum [INN-Latin]
Brand names
  • Sirdalud
  • Ternelin
  • Zanaflex
Brand name mixtures Not Available
Categories
  • Muscle Relaxants
  • Skeletal Muscle Relaxants
  • Anticonvulsants
  • Analgesics
  • Adrenergic alpha-Agonists
  • Muscle Relaxants, Central
  • Parasympatholytics
CAS number 51322-75-9
Weight Average: 253.711
Monoisotopic: 253.018893678
Chemical Formula C9H8ClN5S
InChI Key InChIKey=XFYDIVBRZNQMJC-UHFFFAOYSA-N
InChI
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)
Plain Text
IUPAC Name
5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3-benzothiadiazol-4-amine
SMILES
ClC1=C(NC2=NCCN2)C2=NSN=C2C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzene and Derivatives
  • Halobenzenes
  • Anilines
Substructures
  • Imidazolines
  • Thiadiazoles
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Imidazoles
  • Heterocyclic compounds
  • Guanidines
  • Aromatic compounds
  • Carboxamidines
  • Anilines
Pharmacology
Indication For the management of increased muscle tone associated with spasticity
Pharmacodynamics 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.
Mechanism of action Tizanidine reduces spasticity by increasing presynaptic inhibition of motor neurons through agonist action at a2-adrenergic receptor sites.
Absorption Not Available
Volume of distribution
  • 2.4 L/kg
Protein binding 30%
Metabolism
Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 1A2 5-chloro-4-(guanidino)-2,1,3-benzothiadiazole 0 0
Cytochrome P450 1A2 5-chloro-4-(2-imidazolin-4-on-2-ylamino)-2,1,3-benzothiadiazole 0 0
Route of elimination Approximately 95% of an administered dose is metabolized.
Half life 2.5 hours
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Acorda therapeutics inc
  • Actavis elizabeth llc
  • Actavis totowa llc
  • Alphapharm party ltd
  • Apotex inc
  • Barr laboratories inc
  • Caraco pharmaceutical laboratories ltd
  • Corepharma llc
  • Dr reddys laboratories inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mylan pharmaceuticals inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Zanaflex 6 mg capsule 4.79 USD capsule
Zanaflex 4 mg capsule 3.2 USD capsule
Zanaflex 2 mg capsule 2.52 USD capsule
Zanaflex 4 mg tablet 2.29 USD tablet
Tizanidine hcl 4 mg tablet 1.49 USD tablet
Zanaflex 2 mg tablet 1.42 USD tablet
Tizanidine hcl 2 mg tablet 1.25 USD tablet
Patents
Country Patent Number Approved Expires
United States 6455557 2001-11-28 2021-11-28
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
logP 1.4 PhysProp
Predicted Properties
Property Value Source
water solubility 1.33e-01 g/l ALOGPS
logP 1.60 ALOGPS
logP 2.02 ChemAxon Molconvert
logS -3.28 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 62.20 ChemAxon Molconvert
rotatable bond count 1 ChemAxon Molconvert
refractivity 64.77 ChemAxon Molconvert
polarizability 23.97 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Compound C07452 Link_out
PubChem Compound 5487 Link_out
PubChem Substance 46505373 Link_out
ChemSpider 5287 Link_out
BindingDB 50240671 Link_out
Therapeutic Targets Database DAP000234 Link_out
Drug Product Database 2259893 Link_out
RxList http://www.rxlist.com/cgi/generic/tizanidine.htm Link_out
Drugs.com http://www.drugs.com/tizanidine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Tizanidine Link_out
ATC Codes
  • M03BX02
AHFS Codes
  • 12:20.00
PDB Entries Not Available
FDA label show (145.3 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Alpha-2A adrenergic receptor

Pharmacological action: unknown
Actions: agonist

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

Organism class: human
UniProt ID: P08913 Link_out
Gene: ADRA2A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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. Pubmed

2. Alpha-2B adrenergic receptor

Pharmacological action: yes
Actions: agonist

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

Organism class: human
UniProt ID: P18089 Link_out
Gene: ADRA2B Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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. Pubmed

3. Alpha-2C adrenergic receptor

Pharmacological action: yes
Actions: agonist

Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins

Organism class: human
UniProt ID: P18825 Link_out
Gene: ADRA2C Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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. Pubmed

4. Nischarin

Pharmacological action: no
Actions: agonist

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

Organism class: human
UniProt ID: Q9Y2I1 Link_out
Gene: NISCH Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Rolon PA: Myxoglobulosis of the appendix. Int Surg. 1977 Jun-Jul;62(6-7):355-6. Pubmed
Enzymes

1. Cytochrome P450 1A2

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wang B, Zhou SF: Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218. Pubmed
  2. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  4. Shellenberger MK, Groves L, Shah J, Novack GD: A controlled pharmacokinetic evaluation of tizanidine and baclofen at steady state. Drug Metab Dispos. 1999 Feb;27(2):201-4. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:42

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.