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Identification
NameOrphenadrine
Accession NumberDB01173  (APRD00097)
Typesmall molecule
Groupsapproved
Description

A muscarinic antagonist used to treat drug-induced parkinsonism and to relieve pain from muscle spasm. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
2-(phenyl-o-tolylmethoxy)ethyldimethylamineNot AvailableNot Available
2-methyldiphenhydramineNot AvailableNot Available
o-methyldiphenhydramineNot AvailableNot Available
o-monomethyldiphenhydramineNot AvailableNot Available
β-dimethylaminoethyl 2-methylbenzhydryl etherNot AvailableNot Available
Salts
Name/CAS Structure Properties
Orphenadrine citrate
4682-36-4
Thumb
  • InChI Key: MMMNTDFSPSQXJP-UHFFFAOYNA-N
  • Monoisotopic Mass: 461.204966973
  • Average Mass: 461.5048
DBSALT000400
Orphenadrine hydrochloride
Thumb Not applicable DBSALT001021
Brand names
NameCompany
AntiflexNot Available
BanflexNot Available
BiorphenNot Available
DisipalNot Available
FlexojectNot Available
Mio-RelNot Available
MyolinNot Available
NorflexNot Available
OrfenAceNot Available
OrfroNot Available
Brand mixtures
Brand NameIngredients
DolanOrphenadrine citrate + Acetaminophen
NorgesicOrphenadrine citrate + Acetaminophen
Categories
CAS number83-98-7
WeightAverage: 269.3813
Monoisotopic: 269.177964363
Chemical FormulaC18H23NO
InChI KeyQVYRGXJJSLMXQH-UHFFFAOYSA-N
InChI
InChI=1S/C18H23NO/c1-15-9-7-8-12-17(15)18(20-14-13-19(2)3)16-10-5-4-6-11-16/h4-12,18H,13-14H2,1-3H3
IUPAC Name
dimethyl({2-[(2-methylphenyl)(phenyl)methoxy]ethyl})amine
SMILES
CN(C)CCOC(C1=CC=CC=C1)C1=CC=CC=C1C
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassDiphenylmethanes
Direct parentDiphenylmethanes
Alternative parentsBenzylethers; Toluenes; Tertiary Amines; Dialkyl Ethers; Polyamines
Substituentsbenzylether; toluene; tertiary amine; polyamine; ether; dialkyl ether; organonitrogen compound; amine
Classification descriptionThis compound belongs to the diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Pharmacology
IndicationIndicated for the treatment of Parkinson's disease.
PharmacodynamicsOrphenadrine is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculoskeletal conditions. Orphenadrine is an anticholinergic with a predominantly central effect and only a weak peripheral effect. In addition, it has mild antihistaminic and local anaesthetic properties. Parkinson's syndrome is the consequence of a disturbed balance between cholinergic and dopaminergic neurotransmission in the basal ganglia caused by a decrease in dopamine. Orphenadrine restores the physiological equilibrium and has a favourable effect on the rigidity and tremor of Parkinson's disease and Parkinsonian syndromes. The effect is somewhat less on bradykinesia.
Mechanism of actionOrphenadrine binds and inhibits both histamine H1 receptors and NMDA receptors. It restores the motor disturbances induced by neuroleptics, in particular the hyperkinesia. The dopamine deficiency in the striatum increases the stimulating effects of the cholinergic system. This stimulation is counteracted by the anticholinergic effect of orphenadrine. It may have a relaxing effect on skeletal muscle spasms and it has a mood elevating effect.
AbsorptionOrphenadrine is almost completely absorbed in the gastrointestinal tract.
Volume of distributionNot Available
Protein binding95%
Metabolism

Biotransformation occurs mainly in the liver. Pharmacologically active metabolites are N-demethyl orphenadrine and N,N-didemethyl orphenadrine.

SubstrateEnzymesProduct
Orphenadrine
Not Available
N-demethyl orphenadrineDetails
Orphenadrine
Not Available
N,N-didemethyl orphenadrineDetails
Route of eliminationNot Available
Half life13-20 hours
ClearanceNot Available
ToxicityOral, mouse LD50 = 100 mg/kg; oral, rat LD50 = 255 mg/kg
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9881
Blood Brain Barrier + 0.9134
Caco-2 permeable + 0.8654
P-glycoprotein substrate Substrate 0.6196
P-glycoprotein inhibitor I Inhibitor 0.5825
P-glycoprotein inhibitor II Non-inhibitor 0.6378
Renal organic cation transporter Inhibitor 0.7359
CYP450 2C9 substrate Non-substrate 0.7658
CYP450 2D6 substrate Substrate 0.8918
CYP450 3A4 substrate Substrate 0.6958
CYP450 1A2 substrate Non-inhibitor 0.6363
CYP450 2C9 substrate Non-inhibitor 0.9191
CYP450 2D6 substrate Inhibitor 0.8949
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.9363
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5979
Ames test Non AMES toxic 0.9133
Carcinogenicity Non-carcinogens 0.6341
Biodegradation Not ready biodegradable 0.9422
Rat acute toxicity 2.8405 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.5224
hERG inhibition (predictor II) Inhibitor 0.7052
Pharmacoeconomics
Manufacturers
  • Graceway pharmaceuticals llc
  • Akorn inc
  • Bedford laboratories
  • Watson laboratories inc
  • Ascot hosp pharmaceuticals inc div travenol laboratories inc
  • Gavis pharmaceuticals llc
  • Impax pharmaceuticals
  • Kiel laboratories inc
  • Sandoz inc
  • 3m pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
LiquidIntravenous
TabletOral
Tablet, extended releaseOral
Prices
Unit descriptionCostUnit
Norflex 30 mg/ml ampul14.31USDml
Orphenadrine 30 mg/ml ampule11.25USDml
Orphenadrine Compound-DS 50-770-60 mg tablet2.94USDtablet
Orphenadrine comp forte tablet2.84USDtablet
Norflex er 100 mg tablet2.67USDtablet
Norflex 100 mg tablet sa2.64USDtablet
Orphenadrine Citrate CR 100 mg 12 Hour tablet2.26USDtablet
Orphenadrine er 100 mg tablet2.17USDtablet
Orphenadrine citrate powder1.6USDg
Orphenadrine comp tablet1.31USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point< 25 °CPhysProp
boiling point195 °C at 1.20E+01 mm HgPhysProp
water solubilitySparingly soluble in waterNot Available
logP3.77SANGSTER (1993)
pKa8.91SANGSTER (1994)
Predicted Properties
PropertyValueSource
water solubility3.00e-02 g/lALOGPS
logP3.5ALOGPS
logP4.17ChemAxon
logS-4ALOGPS
pKa (strongest basic)8.87ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count2ChemAxon
hydrogen donor count0ChemAxon
polar surface area12.47ChemAxon
rotatable bond count6ChemAxon
refractivity84.97ChemAxon
polarizability31.83ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Ji D, Sui ZY, Ma YY, Luo F, Cui CL, Han JS: NMDA receptor in nucleus accumbens is implicated in morphine withdrawal in rats. Neurochem Res. 2004 Nov;29(11):2113-20. Pubmed
External Links
ResourceLink
KEGG CompoundC07935
PubChem Compound4601
PubChem Substance46506085
ChemSpider4440
ChEBI7789
ChEMBLCHEMBL900
Therapeutic Targets DatabaseDAP000858
PharmGKBPA450715
Drug Product Database2243559
RxListhttp://www.rxlist.com/cgi/generic/orphen.htm
Drugs.comhttp://www.drugs.com/cdi/orphenadrine.html
WikipediaOrphenadrine
ATC CodesM03BC01N04AB02
AHFS Codes
  • 12:20.00
PDB EntriesNot Available
FDA labelshow(247 KB)
MSDSshow(73.6 KB)
Interactions
Drug Interactions
Drug
DocetaxelOrphenadrine may increase the serum levels and toxicity of docetaxel.
DonepezilPossible antagonism of action
GalantaminePossible antagonism of action
HaloperidolThe anticholinergic increases the risk of psychosis and tardive dyskinesia
RivastigminePossible antagonism of action
TacrineThe therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Orphenadrine, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents.
TrimethobenzamideTrimethobenzamide and Orphenadrine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
TriprolidineTriprolidine and Orphenadrine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.
TrospiumTrospium and Orphenadrine, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.
Food Interactions
  • Take without regard to meals. Avoid alcohol.

Targets

1. Glutamate receptor ionotropic, NMDA 2D

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Glutamate receptor ionotropic, NMDA 2D O15399 Details

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. Pubmed
  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. Pubmed
  3. Kornhuber J, Parsons CG, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P: Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies. J Neural Transm Gen Sect. 1995;102(3):237-46. Pubmed

2. Glutamate receptor ionotropic, NMDA 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Glutamate receptor ionotropic, NMDA 1 Q05586 Details

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. Pubmed
  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. Pubmed
  3. Kornhuber J, Parsons CG, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P: Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies. J Neural Transm Gen Sect. 1995;102(3):237-46. Pubmed

3. Glutamate receptor ionotropic, NMDA 3B

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Glutamate receptor ionotropic, NMDA 3B O60391 Details

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. Pubmed
  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. Pubmed
  3. Kornhuber J, Parsons CG, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P: Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies. J Neural Transm Gen Sect. 1995;102(3):237-46. Pubmed

4. Glutamate receptor ionotropic, NMDA 3A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Glutamate receptor ionotropic, NMDA 3A Q8TCU5 Details

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. Pubmed
  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. Pubmed
  3. Kornhuber J, Parsons CG, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P: Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies. J Neural Transm Gen Sect. 1995;102(3):237-46. Pubmed

5. Histamine H1 receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Histamine H1 receptor P35367 Details

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. Pubmed
  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. Pubmed
  3. Rumore MM, Schlichting DA: Analgesic effects of antihistaminics. Life Sci. 1985 Feb 4;36(5):403-16. Pubmed

6. Sodium-dependent noradrenaline transporter

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium-dependent noradrenaline transporter P23975 Details

References:

  1. Pubill D, Canudas AM, Pallas M, Sureda FX, Escubedo E, Camins A, Camarasa J: Assessment of the adrenergic effects of orphenadrine in rat vas deferens. J Pharm Pharmacol. 1999 Mar;51(3):307-12. Pubmed

7. Sodium channel protein type 10 subunit alpha

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Sodium channel protein type 10 subunit alpha Q9Y5Y9 Details

References:

  1. Pubill D, Canudas AM, Pallas M, Sureda FX, Escubedo E, Camins A, Camarasa J: Assessment of the adrenergic effects of orphenadrine in rat vas deferens. J Pharm Pharmacol. 1999 Mar;51(3):307-12. Pubmed

Enzymes

1. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor inducer

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Peng FC, Lin Wu SW: Metabolism of territrem a in liver microsomes from male wistar rats: 3. Cytochrome p-450 isoforms catalyzing tra metabolism. J Toxicol Environ Health A. 2002 Dec 27;65(24):2163-75. Pubmed
  2. Lin Wu SW, Jean WC, Peng FC, Edwards RJ: Cytochrome P-4503A1 catalyzes the formation of MA1 from territrem a in liver microsomes of 7-week-old female Wistar rats. J Toxicol Environ Health A. 2003 Mar 14;66(5):453-67. Pubmed
  3. Chang TK, Weber GF, Crespi CL, Waxman DJ: Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Cancer Res. 1993 Dec 1;53(23):5629-37. Pubmed
  4. Stresser DM, Dehal SS, Kupfer D: Ring hydroxylation of [o-3H]methoxychlor as a probe for liver microsomal CYP2B activity: potential for in vivo CYP2B assay. Anal Biochem. 1996 Jan 1;233(1):100-7. Pubmed
  5. Murray M, Fiala-Beer E, Sutton D: Upregulation of cytochromes P450 2B in rat liver by orphenadrine. Br J Pharmacol. 2003 Jun;139(4):787-96. Pubmed

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Roos PH, Mahnke A: Metabolite complex formation of orphenadrine with cytochrome P450. Involvement of CYP2C11 and CYP3A isozymes. Biochem Pharmacol. 1996 Jul 12;52(1):73-84. Pubmed

3. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 Details

References:

  1. Sai Y, Dai R, Yang TJ, Krausz KW, Gonzalez FJ, Gelboin HV, Shou M: Assessment of specificity of eight chemical inhibitors using cDNA-expressed cytochromes P450. Xenobiotica. 2000 Apr;30(4):327-43. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13