ORPHENADRINE

Details

Stereochemistry	RACEMIC
Molecular Formula	C18H23NO
Molecular Weight	269.3813
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN(C)CCOC(C1=CC=CC=C1)C2=C(C)C=CC=C2

InChI

InChIKey=QVYRGXJJSLMXQH-UHFFFAOYSA-N

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

HIDE SMILES / InChI

Molecular Formula	C18H23NO
Molecular Weight	269.3813
Charge	0
Count

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 1
E/Z Centers	0
Optical Activity	( + / - )

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Prntlbl.pdf
Curator's Comment: description was created based on several sources, including https://www.drugbank.ca/drugs/DB01173 | https://www.drugs.com/cdi/orphenadrine.html

Orphenadrine is an anticholinergic drug of the ethanolamine antihistamine class used to treat muscle pain and to help with motor control in Parkinson's disease but has largely been superseded by newer drugs. Orphenadrine 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. Orphenadrine 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 anesthetic 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 favorable effect on the rigidity and tremor of Parkinson's disease and Parkinsonian syndromes. Adverse reactions of orphenadrine citrate are mainly due to the mild anticholinergic action of orphenadrine citrate and are usually associated with higher dosage. Dryness of the mouth is usually the first adverse effect to appear. When the daily dose is increased, possible adverse effects include tachycardia, palpitation, urinary hesitancy or retention, blurred vision, dilatation of pupils, increased ocular tension, weakness, nausea, vomiting, headache, dizziness, constipation, drowsiness, hypersensitivity reactions, pruritus, hallucinations, agitation, tremor, gastric irritation and rarely urticaria and other dermatoses

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Histamine H1 receptor 315 Target ID: CHEMBL231 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22793499	Antagonist 2778	97.7 µM [IC50]
Glutamate [NMDA] receptor 125 Target ID: CHEMBL2094124 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9464369	Antagonist 2778	6.0 µM [Ki]
Muscarinic acetylcholine receptor 160 Target ID: CHEMBL2094109 Sources: https://www.ncbi.nlm.nih.gov/pubmed/3353357	Antagonist 2778

Conditions

Condition	Modality	Targets	Highest Phase	Product
Musculoskeletal pain 10 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Prntlbl.pdf	Primary		Approved 8429	DISIPAL Approved Use Orphenadrine citrate extended-release tablets are indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculoskeletal conditions. Launch Date 1957
Quinine-resistant leg cramps 3 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Prntlbl.pdf	Primary		Approved 8429	DISIPAL Approved Use Orphenadrine citrate extended-release tablets are indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculoskeletal conditions. Launch Date 1957

C_max

Value	Dose	Co-administered	Analyte	Population
41.89 ng/mL REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ORPHENADRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
49.19 ng/mL REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ORPHENADRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

AUC

Value	Dose	Co-administered	Analyte	Population
1739.15 ng × h/mL REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ORPHENADRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1772.44 ng × h/mL REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ORPHENADRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

T_1/2

Value	Dose	Co-administered	Analyte	Population
21.02 h REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ORPHENADRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
22.29 h REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ORPHENADRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

F_unbound

Value	Dose	Co-administered	Analyte	Population
7% EXPERIMENT https://www.sciencedirect.com/science/article/pii/S0021967307003342?via%3Dihub			ORPHENADRINE plasma	Homo sapiens

Doses

Dose	Population	Adverse events
500 mg 1 times / day steady, oral Highest studied dose Dose: 500 mg, 1 times / day Route: oral Route: steady Dose: 500 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/1220958	unhealthy, adult Health Status: unhealthy Condition: depression Age Group: adult Sources: https://pubmed.ncbi.nlm.nih.gov/1220958	Sources: https://pubmed.ncbi.nlm.nih.gov/1220958
2 g single, intramuscular Overdose Dose: 2 g Route: intramuscular Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	Other AEs: Toxic reaction (NOS)... Other AEs: Toxic reaction (NOS) (grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf
2 g single, intravenous Overdose Dose: 2 g Route: intravenous Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	Other AEs: Toxic reaction (NOS)... Other AEs: Toxic reaction (NOS) (grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf
2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	Other AEs: Toxic reaction (NOS)... Other AEs: Toxic reaction (NOS) (grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf

AEs

AE	Significance	Dose	Population
Toxic reaction (NOS)	grade 5	2 g single, intramuscular Overdose Dose: 2 g Route: intramuscular Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf
Toxic reaction (NOS)	grade 5	2 g single, intravenous Overdose Dose: 2 g Route: intravenous Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf
Toxic reaction (NOS)	grade 5	2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 810 CYP1A2 1524 CYP2A6 707 CYP2C19 1478 OCT2 647 OCT1 512 MATE1 306 MATE2 263		CYP2B 32

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	partial
CYP2A6 739	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	partial
CYP2C19 1553	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	partial
CYP3A4 1925	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	partial
CYP2B6 1001	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	strong
CYP2C9 1819	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	strong
CYP2D6 1891	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	strong
MATE1 308	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257218/	weak [IC50 65 uM]
MATE2 263	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257218/	weak [IC50 >100 uM]
OCT1 543	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257218/	weak [IC50 >100 uM]
OCT2 648	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257218/	yes [IC50 2.5 uM]
CYP2B 40	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/12813002/	yes

Sourcing

Vendor/Aggregator	ID	URL
Aurora Fine Chemicals LLC	K02.874.612	http://online.aurorafinechemicals.com/info?ID=K02.874.612
BLD Pharm	BD63442	http://www.bldpharm.com/products/83-98-7.html
ChemMol	99164358	http://www.chemmol.com/chemmol/99164358.html
Chemspace	CSSB00020618959	https://chem-space.com/CSSB00020618959
Clearsynth	CS-P-00468	https://www.clearsynth.com/en/CSP00468.html
Smolecule	S603082	https://www.smolecule.com/products/s603082
THE BioTek	bt-364984	https://www.thebiotek.com/product/others/bt-364984
eNovation Chemicals	D111469	https://www.enovationchem.com/ProductDetails.asp?ProductID=D111469
iChemical	EBD71118	http://www.ichemical.com/products/83-98-7.html?utm_source=PubChem&utm_medium=website&utm_campaign=product%20catalogs
mcule	MCULE-7320950210	https://mcule.com/MCULE-7320950210/

PubMed

Title	Date	PubMed
Reversal of orphenadrine-induced ventricular tachycardia with physostigmine.	1991 Nov-Dec	1787292
Orphenadrine prevents 3-nitropropionic acid-induced neurotoxicity in vitro and in vivo.	2001 Feb	11159722
Nefopam, an analogue of orphenadrine, protects against both NMDA receptor-dependent and independent veratridine-induced neurotoxicity.	2002	12373515
Zebrafish embryos express an orthologue of HERG and are sensitive toward a range of QT-prolonging drugs inducing severe arrhythmia.	2003 Dec 15	14678746
Affinity and specificity of N-methyl- D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats.	2003 Feb	12459931
Essential requirements for substrate binding affinity and selectivity toward human CYP2 family enzymes.	2003 Jan 1	12464242
Neuronal sensitization and its behavioral correlates in a rat model of neuropathy are prevented by a cyclic analog of orphenadrine.	2003 Jun	12906743
Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia.	2003 Nov 17	14612892
Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review.	2004 Aug	15276195
Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer.	2004 Jan 12	14710203
Multicentric phase II trial of gemcitabine plus epirubicin plus paclitaxel as first-line chemotherapy in metastatic breast cancer.	2004 Jan 12	14710202
Validated semiquantitative/quantitative screening of 51 drugs in whole blood as silylated derivatives by gas chromatography-selected ion monitoring mass spectrometry and gas chromatography electron capture detection.	2004 Jul 5	15171931
Objective high-frequency tinnitus of middle-ear myoclonus.	2004 Mar	15068524
Primary chemotherapy with gemcitabine, epirubicin and taxol (GET) in operable breast cancer: a phase II study.	2005 Aug 22	16052214
Benzodiazepine prescribing behaviour and attitudes: a survey among general practitioners practicing in northern Thailand.	2005 Jun 23	15975145
Simultaneous determination of ten antihistamine drugs in human plasma using pipette tip solid-phase extraction and gas chromatography/mass spectrometry.	2006	16419026
Restless legs syndrome: diagnosis and review of management options.	2006 Jun	19412460
Torsades de pointes in congenital long QT syndrome following low-dose orphenadrine.	2006 May	16700864
Efficacy and safety of combined piroxicam, dexamethasone, orphenadrine, and cyanocobalamin treatment in mandibular molar surgery.	2006 Sep	16981050
Characterization of antihistamine-human serum protein interactions by capillary electrophoresis.	2007 Apr 20	17339039
Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656.	2007 Dec	17965852
Are there alternatives to the use of quinine to treat nocturnal leg cramps?	2008 Feb	18454580
Genetic and chemical modifiers of a CUG toxicity model in Drosophila.	2008 Feb 13	18270582
Effects of CYP inducers and inhibitors on the pharmacokinetics of intravenous theophylline in rats: involvement of CYP1A1/2 in the formation of 1,3-DMU.	2008 Jan	18088504
Characterization of aconitine-induced block of delayed rectifier K+ current in differentiated NG108-15 neuronal cells.	2008 May	18336846
Evaluation of luciferin-isopropyl acetal as a CYP3A4 substrate for human hepatocytes: effects of organic solvents, cytochrome P450 (P450) inhibitors, and P450 inducers.	2009 Aug	19451401
Fixed drug eruption resulting from fluconazole use: a case report.	2009 Jul 6	19830193
The first asymmetric halogen/metal-exchange reaction: desymmetrization of alcohols with enantiotopic bromoarene substituents.	2009 Jul 6	19492368
Physiological and pathological role of alpha-synuclein in Parkinson's disease through iron mediated oxidative stress; the role of a putative iron-responsive element.	2009 Mar	19399246
Drugs associated with more suicidal ideations are also associated with more suicide attempts.	2009 Oct 2	19798416
(2-Methyl-phen-yl)(phen-yl)methanol.	2010 Jul 31	21588424
7-Benzyloxyresorufin-O-dealkylase activity as a marker for measuring cytochrome P450 CYP3A induction in mouse liver.	2010 Mar 1	19903449
Full recovery from a potentially lethal dose of orphenadrine ingestion using conservative treatment: a case report.	2010 Nov	20200196
Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2.	2011 Jul 14	21599003

Patents

Sample Use Guides

In Vivo Use Guide

Acute musculoskeletal conditions: 100 mg orally twice a day (morning and evening) or 60 mg by intramuscular or intravenous injection. May repeat every 12 hours. Quinine-resistant leg cramps: 100 mg orally at bedtime.

Route of Administration: Other

In Vitro Use Guide

An aliquot (400 mkl) of the brain membrane suspension (0.14 mg of protein), 100 mkl of (-)3H-QNB (0.95 nM) (specific activity 46 Ci/mmol), and 50 mk1 of the competing drugs at various concentrations were preincubated for 10 min. and thereafter incubated for 60 min. at 25C in 50 mM Tris-HC1 buffer (PH 7.4). When binding to heart and lung membranes was studied, 500 nkl of homogenate (protein contents were 0.58 mg and 0.54 mg of rat heart and lung tissue and 0.63 mg of guinea pig lung tissue was added to tubes containing 500 mkl of 50 mM Tris-HC1 buffer (PH 7.4), 100 mk1 of (-)3H-QNB (final concentration 0.4 nM) and 100 mkl of buffer (total binding) or unlabeled Orphenadrine.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 16:06:49 GMT 2023` Edited by `admin` on `Fri Dec 15 16:06:49 GMT 2023`
Record UNII	AL805O9OG9
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ORPHENADRINE

Official Name

English

ORPHENADRIN

Common Name

English

ORPHENADRINE [HSDB]

Common Name

English

ORPHENADRINE [MI]

Common Name

English

(±)-N,N-DIMETHYL-2-((O-METHYL-.ALPHA.-PHENYLBENZYL)OXY)ETHYLAMINE

Common Name

English

orphenadrine [INN]

Common Name

English

Orphenadrine [WHO-DD]

Common Name

English

ETHANAMINE, N,N-DIMETHYL-2-((2-METHYLPHENYL)PHENYLMETHOXY)-, (±)-

Systematic Name

English

MEFENAMINE [JAN]

Common Name

English

ORPHENADRINE [VANDF]

Common Name

English

MIALGIN

Brand Name

English

MEFENAMINE

Common Name

English

Classification Tree Code System Code

WHO-ATC

M03BC51