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class used to treat muscle pain and to help with motor control in Parkinson's disease but has largely been superseded by newer drugs.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 312 Target ID: CHEMBL231 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22793499	Antagonist 2737	97.7 µM [IC50]
Glutamate [NMDA] receptor 123 Target ID: CHEMBL2094124 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9464369	Antagonist 2737	6.0 µM [Ki]
Muscarinic acetylcholine receptor 159 Target ID: CHEMBL2094109 Sources: https://www.ncbi.nlm.nih.gov/pubmed/3353357	Antagonist 2737

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 8307	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 -3.99081603E11
Quinine-resistant leg cramps 3 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Prntlbl.pdf	Primary		Approved 8307	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 -3.99081603E11

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 1532	inhibitor 1695	inhibitor 1789

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 770 CYP1A2 1463 CYP2A6 670 CYP2C19 1410 OCT2 630 OCT1 498 MATE1 302 MATE2 259		CYP2B 32

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1620	inhibitor 3185 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	partial
CYP2A6 702	inhibitor 3185 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	partial
CYP2C19 1484	inhibitor 3185 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	partial
CYP3A4 1857	inhibitor 3185 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	partial
CYP2B6 946	inhibitor 3185 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	strong
CYP2C9 1747	inhibitor 3185 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	strong
CYP2D6 1826	inhibitor 3185 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	strong
MATE1 304	inhibitor 3185 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257218/	weak [IC50 65 uM]
MATE2 259	inhibitor 3185 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257218/	weak [IC50 >100 uM]
OCT1 513	inhibitor 3185 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257218/	weak [IC50 >100 uM]
OCT2 631	inhibitor 3185 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257218/	yes [IC50 2.5 uM]
CYP2B 40	inducer 1515 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
Prochlorperazine in childhood: side-effects.	1977	216517
Involvement of human liver cytochrome P4502B6 in the metabolism of propofol.	2001 Mar	11298076
Non-sustained ventricular tachycardia due to low-dose orphenadrine.	2001 Oct 1	11599527
Metabolism of territrem a in liver microsomes from male wistar rats: 3. Cytochrome p-450 isoforms catalyzing tra metabolism.	2002 Dec 27	12515593
Therapeutic response of benzodiazepine, orphenadrine citrate and occlusal splint association in TMD pain.	2003 Apr	12723857
Upregulation of cytochromes P450 2B in rat liver by orphenadrine.	2003 Jun	12813002
Cytochrome P-4503A1 catalyzes the formation of MA1 from territrem a in liver microsomes of 7-week-old female Wistar rats.	2003 Mar 14	12712632
Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats.	2003 Nov	12851738
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
Multicentric phase II trial of gemcitabine plus epirubicin plus paclitaxel as first-line chemotherapy in metastatic breast cancer.	2004 Jan 12	14710202
Alternatives to levodopa in the initial treatment of early Parkinson's disease.	2005	16156677
Simultaneous determination of ten antihistamine drugs in human plasma using pipette tip solid-phase extraction and gas chromatography/mass spectrometry.	2006	16419026
Pharmacokinetic study of orphenadrine using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).	2006 Jul 24	16580894
Epirubicin/paclitaxel/etoposide in extensive-stage small-cell lung cancer: a phase I-II study.	2006 May 8	16622468
Propofol metabolism is enhanced after repetitive ketamine administration in rats: the role of cytochrome P-450 2B induction.	2006 Sep	16845130
Genetic and chemical modifiers of a CUG toxicity model in Drosophila.	2008 Feb 13	18270582
Demographics of toxic exposures presenting to three public hospital emergency departments in Singapore 2001-2003.	2009 Apr	19390914
The use of antipsychotic and anticholinergic antiparkinson drugs in Norway after the withdrawal of orphenadrine.	2009 Aug	19694744
The use and potential abuse of anticholinergic antiparkinson drugs in Norway: a pharmacoepidemiological study.	2009 Feb	19094158
Fixed drug eruption resulting from fluconazole use: a case report.	2009 Jul 6	19830193
Pharmacokinetics of mirodenafil, a new erectogenic, and its metabolite, SK3541, in rats: involvement of CYP1A1/2, 2B1/2, 2D subfamily, and 3A1/2 for the metabolism of both mirodenafil and SK3541.	2010	20456834
(2-Methyl-phen-yl)(phen-yl)methanol.	2010 Jul 31	21588424
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 16 19:16:25 UTC 2022` Edited by `admin` on `Fri Dec 16 19:16:25 UTC 2022`
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