To PC3 cells, protriptyline (0-70 μM; 24 hours) is cytotoxic [2].

Protriptyline (10 mg/kg; intraperitoneal injection; 21 days; AD rat model) increases spatial learning and maintained memory in STZ-treated rats [3].

Cytotoxicity assay[2]
Cell Types: PC3 Cell
Tested Concentrations: 50, 60 and 70 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: Cell viability diminished in a concentration-dependent manner.

Animal/Disease Models: AD rat model [3]
Doses: 10 mg/kg
Route of Administration: intraperitoneal (ip) injection; 21 days.
Experimental Results: diminished pTau, Aβ42 and BACE-1 levels, neurodegeneration, oxidative stress and glial activation. By reducing NFκB and GFAP expression, improving p-ERK/ERK ratio and increasing BDNF and CREB levels.

Absorption, Distribution and Excretion
Protriptyline is reported to undergo cumulative urinary excretion during 16 days, which accounts for approximately 50% of the total drug administered. The fecal excretion pathway seems to play a minimal role in drug elimination.
EXCRETION...IS RAPID, IN CONTRAST TO LONG LATENCY OF ONSET OF ACTION OF DRUGS. /TRICYCLIC ANTIDEPRESSANTS/
...WELL ABSORBED FROM GI TRACT. ... RAPIDLY DISTRIBUTED & METABOLIZED BY DEMETHYLATION, OXIDATION, & AROMATIC HYDROXYLATION. /IMIPRAMINE/
IN URINE OF RATS TREATED WITH PROTRIPTYLINE... THERE WAS TWICE AS MUCH 10,11-DIHYDRO-10,11-EPOXY-5-(3-METHYLAMINOPROPYL)-5H-DIBENZO[A,D]CYCLOHEPTENE AS 10,11-DIHYDRO-10,11-EPOXY-5-(3-AMINOPROPYL)-5H-DIBENZO[A,D]CYCLOHEPTENE EXCRETED &.../BOTH/ ACCOUNTED FOR 40% OF DOSE OF PROTRIPTYLINE.
MEAN PLASMA LEVELS FOR PROTRIPTYLINE IN PT ALSO ADMIN NITRAZEPAM INDISTINGUISHABLE FROM PT RECEIVING NO NITRAZEPAM. MEAN PLASMA LEVELS FOR PT RECEIVING SODIUM AMYLOBARBITONE SIGNIFICANTLY DECR. EARLY VALUES MAY BE OF PREDICTIVE IMPORTANCE TO PERMIT EARLY DOSE ADJUSTMENT.

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Metabolism / Metabolites
KNOWN OXIDATION OF 10,11 DOUBLE BOND OF PROTRIPTYLINE IN MAN, MINIATURE PIG, & DOG... 2 METABOLITES HAVE BEEN DETECTED WHICH DEMONSTRATE EPOXIDE INTERMEDIATE, NAMELY, DIHYDRODIOL & REARRANGEMENT PRODUCT WHOSE FORMATION IS...CATIONIC INTERMEDIATE...REARRANGING TO DIHYDROANTHRACENIC STRUCTURE.
IN DOGS, MINIATURE PIGS, & MAN, 3 URINARY METABOLITES HAVE NOW BEEN FOUND 10-HYDROXY-N-METHYL-5H-DIBENZO(AD)CYCLOHEPTENE-5-PROPYLAMINE, 10,11-DIHYDROXY-N-METHYL-5H-DIBENZO(AD)CYCLOHEPTENE-5-PROPYLAMINE & 5,10-DIHYDRO-10-FORMYLANTHRACENE-5-PROPYLAMINE.
...PROTRIPTYLINE...AFFORDS URINARY 10,11-OXIDE.
IN URINE OF RATS TREATED WITH PROTRIPTYLINE...2 METABOLITES HAVE BEEN IDENTIFIED...AS 10,11-DIHYDRO-10,11-EPOXY-5-(3-M ETHYLAMINOPROPYL)-5H-DIBENZO[A,D]CYCLOHEPTENE & 10,11-DIHYDRO-10,11-EPOXY-5-(3-AMINOPROPYL)-5H-DIBENZO[A,D]CYCLOHEPTENE.
Route 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.

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Biological Half-Life
AFTER A SINGLE ORAL DOSE OF 30 MG TO 8 SUBJECTS, PEAK LEVELS RANGED FROM 10.4-22.3 NG/ML, 6-12 HR AFTER ADMIN. MEAN T/2 WAS 74.3 HR & RANGED FROM 53.6-91.7 HR IN INDIVIDUAL SUBJECTS.
SINGLE ORAL DOSE OF HCL-SALT ADMIN TO 8 PERSONS. EST 1ST PASS METAB WAS RELATIVELY SMALL, 10-25% OF DOSE, ASSUMING COMPLETE ABSORPTION. MEAN VOL OF DISTRIBUTION 22.5 L/KG & RANGED FROM 15.0-31.2 L/KG. CONCLUSION WAS THAT LONG T/2 IS CORRELATED WITH SMALL 1ST PASS METABOLISM.
PLASMA LEVELS IN 30 PT. AFTER 3.5 WK TREATMENT @ 40 MG/DAY, PLASMA LEVELS RANGED FROM 430-1430 NMOL/L. SINGLE DOSE STUDIES IN 5 VOLUNTEERS SUGGEST THAT VOL OF DISTRIBUTION OF PROTRIPTYLINE SHOWS LITTLE INTERSUBJECT VARIATION. HOWEVER, T/2 MAY VARY, RANGING FROM 54-198 HR.

Toxicity Summary
Protriptyline acts by decreasing the reuptake of norepinephrine and serotonin (5-HT).

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Interactions
Other interactions that also may potentiate the effects of tricyclic antidepressants can result from interference with their metabolism in the liver. This effect has been associated with neuroleptic drugs, methylphenidate, and certain steroids, including oral contraceptives. /Tricyclic antidepressants/
TRICYCLIC ANTIDEPRESSANTS MAY ENHANCE EFFECTS OF ORAL ANTICOAGULANTS. /TRICYCLIC ANTIDEPRESSANTS/
A PARTICULARLY SEVERE, BUT RARE, DRUG-DRUG INTERACTION HAS BEEN NOTED FOLLOWING THE CONCURRENT ADMINISTRATION OF AN MAO INHIBITOR AND A TRICYCLIC ANTIDEPRESSANT. /TRICYCLIC ANTIDEPRESSANTS/
THIS AGENT IS ALSO CONTRAINDICATED IN PT TAKING ANY OF MAO INHIBITOR ANTIDEPRESSANTS, SUCH AS NIALAMIDE, ISOCARBOXAZID, TRANYLCYPROMINE, OR PHENELZINE. /HYDROCHLORIDE/
For more Interactions (Complete) data for PROTRIPTYLINE (32 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 240 mg/kg
LD50 Rat ip 42 mg/kg
LD50 Mouse oral 269 mg/kg
LD50 Mouse ip 67 mg/kg
For more Non-Human Toxicity Values (Complete) data for PROTRIPTYLINE (8 total), please visit the HSDB record page.

[1]. Bansode SB, et, al. Molecular investigations of protriptyline as a multi-target directed ligand in Alzheimer's disease. PLoS One. 2014 Aug 20;9(8):e105196.
[2]. Chang HT, et, al. The mechanism of protriptyline-induced Ca2+ movement and non-Ca2+-triggered cell death in PC3 human prostate cancer cells. J Recept Signal Transduct Res. 2015;35(5):429-34.
[3]. Tiwari V, et, al. Protriptyline improves spatial memory and reduces oxidative damage by regulating NFκB-BDNF/CREB signaling axis in streptozotocin-induced rat model of Alzheimer's disease. Brain Res. 2021 Mar 1;1754:147261.

Protriptyline is a carbotricyclic compound. It has a role as an antidepressant. It derives from a hydride of a dibenzo[a,d][7]annulene.
Protriptyline 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, alpha1-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.
Protriptyline is a Tricyclic Antidepressant.
Protriptyline is a tricyclic antidepressant that was previously widely used in the therapy of major depression. Most of the tricyclic antidepressants have been shown to cause a low rate of mild and transient serum enzyme elevations and rare cases of clinically apparent acute cholestatic liver injury. The potential hepatotoxicity specifically of protriptyline, however, has not been well defined.
Protriptyline 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.
Tricyclic antidepressant similar in action and side effects to IMIPRAMINE. It may produce excitation.
See also: Protriptyline Hydrochloride (has salt form).

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Drug Indication
For the treatment of depression.

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Mechanism of Action
Protriptyline acts by decreasing the reuptake of norepinephrine and serotonin (5-HT).
ACTION OF TRICYCLIC ANTIDEPRESSANTS ON METAB OF CATECHOLAMINES & INDOLEAMINES IN BRAIN HAS CONTRIBUTED SIGNIFICANTLY TO "BIOGENIC AMINE HYPOTHESIS" OF DEPRESSION. ... /ALL/ BLOCK RE-UPTAKE OF NOREPINEPHRINE BY ADRENERGIC NERVE TERMINALS. /DEMETHYLATED ANALOGS ARE MORE POTENT IN THIS ACTION/ /TRICYCLIC ANTIDEPRESSANTS/

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Therapeutic Uses
Adrenergic Uptake Inhibitors; Antidepressive Agents, Tricyclic
TRICYCLIC (DIBENZOCYCLOHEPTENE) ANTIDEPRESSANT DRUG USEFUL IN MGMNT OF ENDOGENOUS & EXOGENOUS DEPRESSIONS. IT ALSO INCR PSYCHOMOTOR ACTIVITY; THIS PROPERTY ENHANCES ITS USE IN WITHDRAWN & ANERGIC PT. /HYDROCHLORIDE/
...MAY BE PARTICULARLY USEFUL IN TREATING DEPRESSED PT WHOSE PREDOMINANT MANIFESTATIONS OF ILLNESS ARE PSYCHOMOTOR RETARDATION, APATHY, & FATIGUE... /HYDROCHLORIDE/
...BECAUSE OF THEIR SEDATIVE PROPERTY. ...MAY BE USEFUL IN INITIAL THERAPY OF DEPRESSED PT WITH SLEEP LOSS... DRUGS DO DECR NUMBER OF AWAKENINGS, INCR STAGE-4 SLEEP, & MARKEDLY DECR REM TIME. /TRICYCLIC ANTIDEPRESSANTS/
For more Therapeutic Uses (Complete) data for PROTRIPTYLINE (8 total), please visit the HSDB record page.

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Drug Warnings
...POSSESSES ANTICHOLINERGIC PROPERTIES &, HENCE, SHOULD NOT BE USED IN PT WITH PYLORIC OBSTRUCTION, GLAUCOMA, OR URINARY RETENTION. /HYDROCHLORIDE/
...THOSE WITH SYMPTOMS OF AGITATION, ANXIETY, & TENSION FREQUENTLY BECOME MORE DISTURBED WITH USE OF PROTRIPTYLINE.
DRUG MAY AGGRAVATE ANXIETY, & IT SHOULD NOT BE USED IN ANXIOUS DEPRESSED PT UNLESS IT IS GIVEN WITH SEDATIVE DRUG, SUCH AS PHENOTHIAZINE WITH SEDATIVE EFFECTS...OR MORE CONVENTIONAL SEDATIVE DRUG... /HYDROCHLORIDE/
TACHYCARDIA & POSTURAL HYPOTENSION OCCUR MORE FREQUENTLY...THAN WITH OTHER ANTIDEPRESSANT DRUGS; HENCE, PT WITH CARDIOVASCULAR DISORDERS & ELDERLY PT SHOULD BE OBSERVED CLOSELY FOR THESE UNTOWARD EFFECTS. /HYDROCHLORIDE/
For more Drug Warnings (Complete) data for PROTRIPTYLINE (28 total), please visit the HSDB record page.

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Pharmacodynamics
Protriptyline is a tricyclic antidepressant. It was thought that tricyclic antidepressants work by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin by nerve cells. The effectiveness of antidepressants appear after approximately two weeks following recommended adminsitration schedule. Gradual changes are thought to occur in the cerebral cortex and hippocampus, involved in emotion regulation as part of the limbic system, as receptor sensitivity is enhanced. While α₁ and β₁ receptors are sensitized, α₂ receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also reported to alter the perceptions of pain, including neuropathic or neuralgic pain, so they may exhibit analgesic properties. The mechanism of action behind this analgesic property is not fully understood; however, it is thought to involve modulation of endogenous opioid systems in the CNS via an indirect serotonergic route. Tricyclic antidepressants are also effective in relieving migraine prophylaxis, but not in abortion of acute migraine attack, potentially via their serotonergic effects.

C19H21N

263.167

438-60-8

Protriptyline hydrochloride;1225-55-4;Protriptyline-d3;136765-50-9

4976

Typically exists as solid at room temperature

1.026 g/cm3

407.7ºC at 760 mmHg

169-171 °C (Protriptyline HCl)
Max absorption 290 nm (e= 13,311); MP: 169-171 °C; crystals from isopropanol- ethyl ether /hydrochloride/
169 - 171 °C (protriptyline hydrochloride)

198.3ºC

4.692

1

1

4

20

296

0

CNCCCC1C2=CC=CC=C2C=CC3=CC=CC=C31

BWPIARFWQZKAIA-UHFFFAOYSA-N

InChI=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

N-methyl-3-(2-tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,9,11,13-heptaenyl)propan-1-amine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)