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Record Information
Version2.0
Creation Date2009-07-21 20:26:40 UTC
Update Date2014-12-24 20:25:51 UTC
Accession NumberT3D2759
Identification
Common NameProtriptyline
ClassSmall Molecule
DescriptionProtriptyline hydrochloride is a dibenzocycloheptene-derivative tricyclic antidepressant (TCA). TCAs are structurally similar to phenothiazines. They contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, protriptyline does not affect mood or arousal, but may cause sedation. In depressed individuals, protriptyline exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. In addition, TCAs down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine H1 receptors, α1-adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. See toxicity section below for a complete listing of side effects. Protriptyline may be used for the treatment of depression.
Compound Type
  • Adrenergic Uptake Inhibitor
  • Amine
  • Antidepressant
  • Antidepressive Agent, Tricyclic
  • Drug
  • Metabolite
  • Norepinephrine Reuptake Inhibitor
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
3-(5H-Dibenzo[a,D]cyclohepten-5-yl)-N-methyl-1-propanamine
3-(5H-dibenzo[a,d][7]annulen-5-yl)-N-methylpropan-1-amine
5-(3-Methylaminopropyl)-5H-dibenzo[a,D]cycloheptene
7-(3-Methylaminopropyl)-1,2:5,6-dibenzocycloheptatriene
Amimetilina
N-Methyl-5H-dibenzo[a,D]cycloheptene-5-propanamine
N-Methyl-5H-dibenzo[a,D]cycloheptene-5-propylamine
Protriptilina
Protriptylin
Protriptyline Hydrochloride
Protriptylinum
Protryptyline
Triptil
Vivactil
Chemical FormulaC19H21N
Average Molecular Mass263.377 g/mol
Monoisotopic Mass263.167 g/mol
CAS Registry Number438-60-8
IUPAC Namemethyl(3-{tricyclo[9.4.0.0³,⁸]pentadeca-1(15),3,5,7,9,11,13-heptaen-2-yl}propyl)amine
Traditional Nameprotriptyline
SMILESCNCCCC1C2=CC=CC=C2C=CC2=CC=CC=C12
InChI IdentifierInChI=1S/C19H21N/c1-20-14-6-11-19-17-9-4-2-7-15(17)12-13-16-8-3-5-10-18(16)19/h2-5,7-10,12-13,19-20H,6,11,14H2,1H3
InChI KeyInChIKey=BWPIARFWQZKAIA-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as dibenzocycloheptenes. Dibenzocycloheptenes are compounds containing a dibenzocycloheptene moiety, which consists of two benzene rings connected by a cycloheptene ring.
KingdomOrganic compounds
Super ClassBenzenoids
ClassDibenzocycloheptenes
Sub ClassNot Available
Direct ParentDibenzocycloheptenes
Alternative Parents
Substituents
  • Dibenzocycloheptene
  • Aralkylamine
  • Secondary amine
  • Secondary aliphatic amine
  • Organic nitrogen compound
  • Organopnictogen compound
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Amine
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point169-171°C (Protriptyline HCl)
Boiling PointNot Available
Solubility1.04 mg/L
LogP4.7
Predicted Properties
PropertyValueSource
Water Solubility0.00023 g/LALOGPS
logP4.65ALOGPS
logP4.5ChemAxon
logS-6.1ALOGPS
pKa (Strongest Basic)10.54ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area12.03 ŲChemAxon
Rotatable Bond Count4ChemAxon
Refractivity87.3 m³·mol⁻¹ChemAxon
Polarizability31.6 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0006-9040000000-6498574fa1f4eead1816JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-03e9-0090000000-2ab870bf797378caf1c5JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-01q9-2190000000-b7468843989ba53316aaJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-052f-8890000000-d9505145b3d35ed27be8JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03di-0090000000-13fe8faae8c2bed47e30JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-03di-1090000000-8781e71c0e0ae6ea19beJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-001l-5490000000-349b95c342d47d80f512JSpectraViewer
MSMass Spectrum (Electron Ionization)splash10-006x-8910000000-ec599ee02d998905757eJSpectraViewer | MoNA
Toxicity Profile
Route of ExposureOral
Mechanism of ToxicityProtriptyline acts by decreasing the reuptake of norepinephrine and serotonin (5-HT).
MetabolismRoute of Elimination: Cumulative urinary excretion during 16 days accounted for approximately 50% of the drug. The fecal route of excretion did not seem to be important.
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the treatment of depression.
Minimum Risk LevelNot Available
Health EffectsProtriptyline shares side effects common to all tricyclic antidepressants. The most frequent of these are dry mouth, constipation, urinary retention, increased heart rate, sedation, irritability, dizziness, decreased coordination, anxiety, blood disorders, confusion, decreased libido, dizziness, flushing, headache, impotence, insomnia, low blood pressure, nightmares, rapid or irregular heartbeat, rash, seizures, sensitivity to sunlight, stomach and intestinal problems. Other more complicated side effects include; chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling; sudden numbness or weakness, especially on one side of the body; sudden headache, confusion, problems with vision, speech, or balance; hallucinations, or seizure (convulsions); easy bruising or bleeding, unusual weakness; restless muscle movements in your eyes, tongue, jaw, or neck; urinating less than usual or not at all; extreme thirst with headache, nausea, vomiting, and weakness; or feeling light-headed or fainting. Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. (Wikipedia)
SymptomsWithdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia.
TreatmentDry mouth, if severe to the point of causing difficulty speaking or swallowing, may be managed by dosage reduction or temporary discontinuation of the drug. Patients may also chew sugarless gum or suck on sugarless candy in order to increase the flow of saliva. Some artificial saliva products may give temporary relief. Men with prostate enlargement who take protriptyline may be especially likely to have problems with urinary retention. Symptoms include having difficulty starting a urine flow and more difficulty than usual passing urine. In most cases, urinary retention is managed with dose reduction or by switching to another type of antidepressant. In extreme cases, patients may require treatment with bethanechol, a drug that reverses this particular side effect. As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital monitoring is required as soon as possible. (Wikipedia)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00344
HMDB IDHMDB14488
PubChem Compound ID4976
ChEMBL IDCHEMBL668
ChemSpider ID4805
KEGG IDC07408
UniProt IDNot Available
OMIM ID
ChEBI ID8597
BioCyc IDNot Available
CTD IDNot Available
Stitch IDProtriptyline
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkProtriptyline
References
Synthesis ReferenceNot Available
MSDST3D2759.pdf
General References
  1. Drugs.com [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Norepinephrine:sodium symporter activity
Specific Function:
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:
SLC6A2
Uniprot ID:
P23975
Molecular Weight:
69331.42 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.00141 uMNot AvailableBindingDB 50176062
Inhibitory0.002 uMNot AvailableBindingDB 50176062
Inhibitory0.0023 uMNot AvailableBindingDB 50176062
IC500.0017 uMNot AvailableBindingDB 50176062
Dissociation0.0014 uMNot AvailableBindingDB 50176062
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. [17139284 ]
  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. [17016423 ]
  3. Altenbach RJ, Black LA, Strakhova MI, Manelli AM, Carr TL, Marsh KC, Wetter JM, Wensink EJ, Hsieh GC, Honore P, Garrison TR, Brioni JD, Cowart MD: Diaryldiamines with dual inhibition of the histamine H(3) receptor and the norepinephrine transporter and the efficacy of 4-(3-(methylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol in pain. J Med Chem. 2010 Nov 11;53(21):7869-73. doi: 10.1021/jm100666w. [20945906 ]
  4. Mladenova G, Annedi SC, Ramnauth J, Maddaford SP, Rakhit S, Andrews JS, Zhang D, Porreca F: First-in-class, dual-action, 3,5-disubstituted indole derivatives having human nitric oxide synthase (nNOS) and norepinephrine reuptake inhibitory (NERI) activity for the treatment of neuropathic pain. J Med Chem. 2012 Apr 12;55(7):3488-501. doi: 10.1021/jm300138g. Epub 2012 Apr 4. [22420844 ]
  5. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [9537821 ]
  6. Dolusic E, Larrieu P, Moineaux L, Stroobant V, Pilotte L, Colau D, Pochet L, Van den Eynde B, Masereel B, Wouters J, Frederick R: Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators. J Med Chem. 2011 Aug 11;54(15):5320-34. doi: 10.1021/jm2006782. Epub 2011 Jul 18. [21726069 ]
General Function:
Serotonin:sodium symporter activity
Specific Function:
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.
Gene Name:
SLC6A4
Uniprot ID:
P31645
Molecular Weight:
70324.165 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.0196 uMNot AvailableBindingDB 50176062
References
  1. McDougle CJ, Epperson CN, Price LH, Gelernter J: Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. Mol Psychiatry. 1998 May;3(3):270-3. [9672904 ]
  2. Rouillon F, Blachier C, Dreyfus JP, Bouhassira M, Allicar MP: [Pharmaco-epidemiologic study of the use of antidepressant drugs in the general population]. Encephale. 1996 May;22 Spec No 1:39-48. [8767026 ]
  3. Frazer A, Daws LC: Serotonin transporter function in vivo: assessment by chronoamperometry. Ann N Y Acad Sci. 1998 Dec 15;861:217-29. [9928259 ]
  4. Daws LC, Toney GM, Gerhardt GA, Frazer A: In vivo chronoamperometric measures of extracellular serotonin clearance in rat dorsal hippocampus: contribution of serotonin and norepinephrine transporters. J Pharmacol Exp Ther. 1998 Aug;286(2):967-76. [9694957 ]
  5. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [9537821 ]
General Function:
G-protein coupled adenosine receptor activity
Specific Function:
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase. Possible role in reproduction.
Gene Name:
ADORA3
Uniprot ID:
P0DMS8
Molecular Weight:
36184.175 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.0011 uMNot AvailableBindingDB 50176062
References
  1. Minetti P, Tinti MO, Carminati P, Castorina M, Di Cesare MA, Di Serio S, Gallo G, Ghirardi O, Giorgi F, Giorgi L, Piersanti G, Bartoccini F, Tarzia G: 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists. Design, synthesis, and pharmacological characterization. J Med Chem. 2005 Nov 3;48(22):6887-96. [16250647 ]
General Function:
Monoamine transmembrane transporter activity
Specific Function:
Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:
SLC6A3
Uniprot ID:
Q01959
Molecular Weight:
68494.255 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory2.1 uMNot AvailableBindingDB 50176062
References
  1. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [9537821 ]