MAPROTILINE MESYLATE

US Previously Marketed

Details

Stereochemistry	ACHIRAL
Molecular Formula	C20H23N.CH4O3S
Molecular Weight	373.509
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CS(O)(=O)=O.CNCCCC12CCC(C3=CC=CC=C13)C4=CC=CC=C24

InChI

InChIKey=IUOFVKUAHKGVIO-UHFFFAOYSA-N

InChI=1S/C20H23N.CH4O3S/c1-21-14-6-12-20-13-11-15(16-7-2-4-9-18(16)20)17-8-3-5-10-19(17)20;1-5(2,3)4/h2-5,7-10,15,21H,6,11-14H2,1H3;1H3,(H,2,3,4)

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf

Maprotiline is a tetracyclic antidepressant with similar pharmacological properties to tricyclic antidepressants (TCAs). Similar to TCAs, maprotiline inhibits neuronal norepinephrine reuptake, possesses some anticholinergic activity, and does not affect monoamine oxidase activity. It differs from TCAs in that it does not appear to block serotonin reuptake. Maprotiline may be used to treat depressive affective disorders, including dysthymic disorder (depressive neurosis) and major depressive disorder. Maprotiline is effective at reducing symptoms of anxiety associated with depression. The mechanism of action of maprotiline is not precisely known. It does not act primarily by stimulation of the central nervous system and is not a monoamine oxidase inhibitor. The postulated mechanism of maprotiline is that it acts primarily by potentiation of central adrenergic synapses by blocking reuptake of norepinephrine at nerve endings. This pharmacologic action is thought to be responsible for the drug’s antidepressant and anxiolytic effects. The mean time to peak is 12 hours. The half-life of elimination averages 51 hours.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Norepinephrine transporter 191 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17984940	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Dysthymic disorder 3 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	Primary		Approved 8429	MAPROTILINE HYDROCHLORIDE Approved Use Maprotiline hydrochloride tablets are indicated for the treatment of depressive illness in patients with depressive neurosis (dysthymic disorder) and manic depressive illness, depressed type (major depressive disorder). Maprotiline is also effective for the relief of anxiety associated with de pression. Launch Date 1988
Major depressive disorder 173 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	Primary		Approved 8429	MAPROTILINE HYDROCHLORIDE Approved Use Maprotiline hydrochloride tablets are indicated for the treatment of depressive illness in patients with depressive neurosis (dysthymic disorder) and manic depressive illness, depressed type (major depressive disorder). Maprotiline is also effective for the relief of anxiety associated with de pression. Launch Date 1988

C_max

Value	Dose	Co-administered	Analyte	Population
139 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/6775331	125 mg single, oral dose: 125 mg route of administration: Oral experiment type: SINGLE co-administered:		MAPROTILINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: FASTED
17.6 ng/mL DRUG LABEL https://pdf.hres.ca/dpd_pm/00014410.PDF	75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered:		MAPROTILINE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
3244 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/6775331	125 mg single, oral dose: 125 mg route of administration: Oral experiment type: SINGLE co-administered:		MAPROTILINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
44.3 h DRUG LABEL https://pdf.hres.ca/dpd_pm/00014410.PDF	75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered:		MAPROTILINE plasma	Homo sapiens

Doses

Dose	Population	Adverse events
75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	Other AEs: Nervousness, Anxiety... Other AEs: Nervousness (6%) Anxiety (3%) Insomnia (2%) Agitation (2%) Drowsiness (16%) Dizziness (8%) Tremor (3%) Dry mouth (22%) Constipation (6%) Blurred vision (4%) Nausea (2%) Weakness (4%) Headache (4%) Fatigue (4%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf

AEs

AE	Significance	Dose	Population
Drowsiness	16%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Agitation	2%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Insomnia	2%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Nausea	2%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Dry mouth	22%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Anxiety	3%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Tremor	3%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Blurred vision	4%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Fatigue	4%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Headache	4%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Weakness	4%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Constipation	6%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Nervousness	6%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf
Dizziness	8%	75 mg 1 times / day multiple, oral (starting) Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf	unhealthy Health Status: unhealthy Condition: depressive illness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/072285s021lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737		substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP1A2 1054

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
Ca2+ channels 60	activator 214 Sources: https://pubmed.ncbi.nlm.nih.gov/23219590/; https://pubmed.ncbi.nlm.nih.gov/15207657/	likely

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12071336/	likely	likely (co-administration study) Comment: Relevant inhibition of the desmethylmaprotiline formation rate was observed in incubations with quinidine, furafylline and ketoconazole only Sources: https://pubmed.ncbi.nlm.nih.gov/12071336/
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12071336/	yes	likely (co-administration study) Comment: Relevant inhibition of the desmethylmaprotiline formation rate was observed in incubations with quinidine, furafylline and ketoconazole only Sources: https://pubmed.ncbi.nlm.nih.gov/12071336/
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12071336/	yes	likely (co-administration study) Comment: Relevant inhibition of the desmethylmaprotiline formation rate was observed in incubations with quinidine, furafylline and ketoconazole only Sources: https://pubmed.ncbi.nlm.nih.gov/12071336/

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/16423345/; https://pubmed.ncbi.nlm.nih.gov/16736158/

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY34088	https://www.001chemical.com/chem/10262-69-8
3B Scientific (Wuhan) Corp	3B2-6214	http://www.3bsc.com/index/pro_info.php?id=106789
AK Scientific, Inc. (AKSCI)	0643AA	http://www.aksci.com/item_detail.php?cat=0643AA
Alichem	229000247	http://www.alichem.com/en/products/10262-69-8.html
BOC Sciences	136765-39-4	https://www.bocsci.com/maprotiline-d3-cas-136765-39-4-item-80161.html
BioSynth	J-000745	https://www.biosynth.com/en/products/all-products/products/J-000745.html
Boerchem	BC204740	http://www.boerchem.com/?product_34465.html
ChemMol	30102260	http://www.chemmol.com/chemmol/30102260.html
ChemMol	44001931	http://www.chemmol.com/chemmol/44001931.html
Chemspace	CSSB00020590893	https://chem-space.com/CSSB00020590893
Clearsynth	CS-O-01861	https://www.clearsynth.com/en/CSO01861.html
Hairui	HR108004	http://www.hairuichem.com/en/product/10262-69-8.html
Molcore	MC34088	https://www.molcore.com/product/10262-69-8
OChem	14834	http://www.ocheminc.com/index.php?act=psearch&pid=262M698
Parchem	29339	http://www.parchem.com/chemical-supplier-distributor/Maprotiline-019339.aspx
Smolecule	S593121	https://www.smolecule.com/products/s593121
THE BioTek	bt-291925	https://www.thebiotek.com/product/others/bt-291925
Yuhao Chemical	YH21686	http://www.chemyuhao.com/10262-69-8.html

PubMed

Title	Date	PubMed
[Depression in epilepsy: symptom or syndrome?].	2002 Nov-Dec	12645397
[Current views on migraine and anti-migraine preparations].	2003	14598505
Differential effects of antidepressants on glucocorticoid receptors in human primary blood cells and human monocytic U-937 cells.	2003 Apr	12655328
Optimised procedures for the reversed-phase liquid chromatographic analysis of formulations containing tricyclic antidepressants.	2003 Apr 24	12852450
Analysis of eighteen antidepressants, four atypical antipsychotics and active metabolites in serum by liquid chromatography: a simple tool for therapeutic drug monitoring.	2003 Aug 25	12888196
Differential effects of K(ATP) channel blockers on [(3)H]-noradrenaline overflow after short- and long-term exposure to (+)-oxaprotiline or desipramine.	2003 Feb	12595958
Chronic treatment with antidepressants decreases intraoperative core hypothermia.	2003 Jul	12818981
Bi-phasic change in BDNF gene expression following antidepressant drug treatment.	2003 Jun	12726822
Neuroleptic malignant-like syndrome due to donepezil and maprotiline.	2003 Mar 25	12654986
Current perception thresholds of patients with long-term administration of maprotiline.	2003 Mar-Apr	12734762
Olanzapine in the treatment-resistant, combat-related PTSD--a series of case reports.	2003 May	12752037
Tricyclic antidepressants as long-acting local anesthetics.	2003 May	12749958
In vivo measurement of the serotonin transporter with (S)-([18F]fluoromethyl)-(+)-McN5652.	2003 Nov	12931143
Effects of some antidepressant drugs on tryptaminergic responses of the rat jejunum.	2003 Oct	12928582
A comparative solid-phase extraction study for the simultaneous determination of fluoxetine, amitriptyline, nortriptyline, trimipramine, maprotiline, clomipramine, and trazodone in whole blood by capillary gas-liquid chromatography with nitrogen-phosphorus detection.	2003 Sep	14516488
[Placebo to antidepressant effects ratio by electroencephalographic data].	2004	15581036
Current use of selective serotonin reuptake inhibitors and risk of acute myocardial infarction.	2004	15554748
Increased subcutaneous abdominal tissue norepinephrine levels in patients with anorexia nervosa: an in vivo microdialysis study.	2004	15312000
Effect of the antidepressant maprotiline on calcium movement and the viability of renal tubular cells.	2004 Aug	15057508
Human liver aldehyde oxidase: inhibition by 239 drugs.	2004 Jan	14681337
Effect of the antidepressant maprotiline on Ca2+ movement and proliferation in human prostate cancer cells.	2004 Jul	15236632
[Determination of amitriptyline and maprotiline in health foods by GC-MS].	2004 May	15712928
[Comparative observation on efficacy of jieyu pill and maprotiline in treating depression].	2004 May	15199625
Serotonin syndrome due to association of venlafaxine, maprotiline and reboxetine.	2004 Nov	15504661
Risk of fetal exposure to tricyclic antidepressants.	2004 Oct	15507199
Serotonin and noradrenaline reuptake inhibitors in animal models of pain.	2004 Oct	15378668
Clinical study on electro-acupuncture treatment for 30 cases of mental depression.	2004 Sep	15510791
Tricyclic antidepressants, QT interval prolongation, and torsade de pointes.	2004 Sep-Oct	15345781
Frontotemporal arachnoid cyst connected to relapsing stupor.	2004 Winter	14990772
Contribution of sleep research to the development of new antidepressants.	2005	16416706
Dose-response relationship of recent antidepressants in the short-term treatment of depression.	2005	16156383
The AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants.	2005	16156382
Screening antidepressants in the chick separation-stress paradigm.	2005 Aug	15778882
Synthesis and C-11 labeling of three potent norepinephrine transporter selective ligands ((R)-nisoxetine, lortalamine, and oxaprotiline) for comparative PET studies in baboons.	2005 Aug 1	15914010
Reduction of Submissive Behavior Model for antidepressant drug activity testing: study using a video-tracking system.	2005 Dec	16286818
Development of a solid phase extraction for 13 'new' generation antidepressants and their active metabolites for gas chromatographic-mass spectrometric analysis.	2005 Dec 9	16314157
Analgesic therapy in postherpetic neuralgia: a quantitative systematic review.	2005 Jul	16013891
[Evaluation of antidepressant activity in a model of depressionlike state due to social isolation in rats].	2005 Jul-Aug	16193649
Effect of pharmacologically selective antidepressants on serotonin uptake in rat platelets.	2005 Mar	15900091
[Detection of maprotiline and proserine in forensic medical examination of cadaver].	2005 Mar-Apr	15881143
The monoamine-mediated antiallodynic effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a rat model of neuropathic pain.	2005 May	15845695
Citalopram associated with acute angle-closure glaucoma: case report.	2005 Oct 4	16202173
Changes in AMPA subunit expression in the mouse brain after chronic treatment with the antidepressant maprotiline: a link between noradrenergic and glutamatergic function?	2006 Apr	16320045
A fully automated turbulent-flow liquid chromatography-tandem mass spectrometry technique for monitoring antidepressants in human serum.	2006 Feb	16418706
Inhibition of cardiac HERG potassium channels by antidepressant maprotiline.	2006 Feb 15	16423345
Dopamine release in human neocortical slices: characterization of inhibitory autoreceptors and of nicotinic acetylcholine receptor-evoked release.	2006 Jan 30	16377444
Are the effects of the antidepressants amitriptyline, maprotiline, and fluoxetine on inhibitory avoidance state-dependent?	2006 Jan 6	16159672
Increasing synaptic noradrenaline, serotonin and histamine enhances in vivo binding of phosphodiesterase-4 inhibitor (R)-[11C]rolipram in rat brain, lung and heart.	2006 Jun 20	16499932
Age-dependent interactive changes in serotonergic and noradrenergic cortical axon terminals in F344 rats.	2006 Mar	16406149
Phosducin-like protein levels in leukocytes of patients with major depression and in rat cortex: the effect of chronic treatment with antidepressants.	2006 Mar 30	16510194

Patents

Sample Use Guides

In Vivo Use Guide

Initial Adult Dosage: 75 mg daily is suggested for outpatients with mild to moderate depression. However, in some patients, particularly the elderly, an initial dosage of 25 mg daily may be used. Because of the long half-life of maprotiline, the initial dosage should be maintained for 2 weeks. The dosage may then be increased gradually in 25 mg increments as required and tolerated. In most outpatients a maximum dose of 150 mg daily More severely depressed, hospitalized patients should be given an initial daily dose of 100 mg to 150 mg which may be gradually increased as required and tolerated. Most hospitalized patients with moderate to severe depression respond to a daily dose of 150 mg although dosages as high as 225 mg may be re quired in some cases. Daily dosage of 225 mg should not be exceeded. Elderly Patients: In general, lower dosages are recommended for patients over 60 years of age. Dosages of 50 mg to 75 mg daily are usually satisfactory as maintenance therapy for elderly patients who do not tolerate higher amounts.

Route of Administration: Oral

In Vitro Use Guide

Maprotiline inhibited hERG currents with an IC(50) of 8.2 micromol/l in HEK cells and 29.2 micromol/l in Xenopus oocytes

Name

Type

Language

MAPROTILINE MESYLATE

Common Name

English

Maprotiline mesilate [WHO-DD]

Common Name

English

MAPROTILINE MESILATE

Common Name

English

Code System Code Type Description

FDA UNII

22P65W41V0