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

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class used to treat muscle pain and to help with motor control in Parkinson's disease but has largely been superseded by newer drugs.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
[Pilot study on the effects of an antiparkinson anticholinergic agent during depressive conditions].	1975	1220958
In vitro long-term cytotoxicity testing of 27 MEIC chemicals on Hep G2 cells and comparison with acute human toxicity data.	2001 Apr	11287174
Acute intoxication with orphenadrine and clozapine.	2001 Nov 15	11731191
Nefopam, an analogue of orphenadrine, protects against both NMDA receptor-dependent and independent veratridine-induced neurotoxicity.	2002	12373515
Essential requirements for substrate binding affinity and selectivity toward human CYP2 family enzymes.	2003 Jan 1	12464242
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
300-Hz subthalamic oscillations in Parkinson's disease.	2003 Oct	12937087
Objective high-frequency tinnitus of middle-ear myoclonus.	2004 Mar	15068524
[Comparative study between botulin toxin and bupivacaine for triggering-points infiltration in chronic myofascial syndrome.].	2005 Apr	19471828
Benzodiazepine prescribing behaviour and attitudes: a survey among general practitioners practicing in northern Thailand.	2005 Jun 23	15975145
Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous ipriflavone in rats.	2006 Apr	16597362
OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice.	2006 Nov	17132069
Effects of enzyme inducers and inhibitors on the pharmacokinetics of metformin in rats: involvement of CYP2C11, 2D1 and 3A1/2 for the metabolism of metformin.	2006 Oct	16940989
Acute adverse cutaneous reaction after the concomitant use of venlafaxine and orphenadrine citrate plus paracetamol in a depressed patient.	2006 Sep	16922966
Anticholinergic drug-induced delirium in an elderly Alzheimer's dementia patient.	2007	17317453
Evaluation of enantioselective binding of basic drugs to plasma by ACE.	2007 Aug	17661317
Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656.	2007 Dec	17965852
[Enzyme kinetics of schizandrin metabolism and sex differences in rat liver microsomes].	2007 Jul	17882956
Pharmacologic profiling of human and rat cytochrome P450 1A1 and 1A2 induction and competition.	2008 Dec	18493746
Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine.	2009 Apr	19217209
Influence of orphenadrine upon the protective activity of various antiepileptics in the maximal electroshock-induced convulsions in mice.	2009 Jul-Aug	19815957
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
Determination of orphenadrine plasma levels using HPLC with diode array detection and a novel solid-phase extraction procedure in psychiatric patients.	2009 Oct 15	19524386
Drugs associated with more suicidal ideations are also associated with more suicide attempts.	2009 Oct 2	19798416
Orphenadrinium picrate.	2010 Dec 18	21522693
(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
Opiate sparing effect of fixed combination of diclophenac and orphenadrine after unilateral total hip arthroplasty: A double-blind, randomized, placebo-controlled, multi-centre clinical trial.	2010 Nov	20890791
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.

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