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 has been reported to be excreted cumulatively in the urine over 16 days, accounting for approximately 50% of the total dose. Fecal excretion appears to play a minimal role in drug clearance. Excretion is rapid, a stark contrast to the drug's slow onset of action. /Tricyclic antidepressants/ …easily absorbed from the gastrointestinal tract. …rapidly distributed and metabolized via demethylation, oxidation, and aromatic hydroxylation. In the urine of rats treated with protriptyline, the excretion of 10,11-dihydro-10,11-epoxy-5-(3-methylaminopropyl)-5H-dibenzo[A,D]cycloheptene was twice that of 10,11-dihydro-10,11-epoxy-5-(3-aminopropyl)-5H-dibenzo[A,D]cycloheptene, and the two together accounted for 40% of the protriptyline dose. Patients taking nitrazepam concurrently did not show a significant difference in mean plasma concentrations of protriptyline compared to those not taking nitrazepam. Patients receiving sodium pentobarbital showed a significantly lower mean plasma concentration. Early values may be predictive, allowing for early dose adjustments.

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Metabolisms/Metabolites
It is known that the 10,11 double bond of protriptyline undergoes oxidation in humans, miniature pigs, and dogs… Two metabolites have been detected, indicating the presence of an epoxide intermediate, namely dihydrodiol, and a rearrangement product formed via… a cationic intermediate… rearranged to a dihydroanthracene structure.
Three urinary metabolites have been identified in dogs, miniature pigs, and humans: 10-hydroxy-N-methyl-5H-dibenzo[A,D]cycloheptene-5-propanediamine, 10,11-dihydroxy-N-methyl-5H-dibenzo[A,D]cycloheptene-5-propanediamine, and 5,10-dihydroxy-10-formylanthracene-5-propanediamine.
...Protriptyline...can lead to the presence of 10,11-oxides in urine.
In the urine of rats treated with protriptyline...two metabolites have been identified...10,11-dihydroxy-10,11-epoxy-5-(3-methylethylaminopropyl)-5H-dibenzo[A,D]cycloheptene and 10,11-dihydro-10,11-epoxy-5-(3-aminopropyl)-5H-dibenzo[A,D]cycloheptene.
Elimination pathway: Approximately 50% of the total drug is excreted in the urine over 16 days. Fecal excretion does not appear to be significant.
Biological half-life

In 8 subjects, after a single oral dose of 30 mg, the peak plasma concentrations ranged from 10.4 to 22.3 ng/ml 6–12 hours post-administration. The mean half-life (T/2) was 74.3 hours, with individual subjects experiencing a range of 53.6–91.7 hours. Eight subjects underwent a single oral administration of protriptyline hydrochloride. Assuming complete absorption, the estimated first-pass metabolism was relatively small, ranging from 10–25% of the dose. The mean volume of distribution was 22.5 L/kg, ranging from 15.0–31.2 L/kg. The conclusion is that a longer half-life is associated with a smaller first-pass metabolism. Plasma drug concentrations in 30 subjects: After 3.5 weeks of treatment with 40 mg daily, plasma concentrations ranged from 430–1430 nanomoles/L. A single-dose study in five volunteers showed little inter-individual variation in the volume of distribution of protriptyline. However, the half-life (T2) may vary, ranging from 54–198 hours.

Toxicity Summary
Protriptyline works by reducing the reuptake of norepinephrine and serotonin (5-HT). Interactions Other interactions that may enhance the effects of tricyclic antidepressants may stem from interference with their metabolism in the liver. This effect is associated with antipsychotics, methylphenidate, and certain steroids, including oral contraceptives. /Tricyclic Antidepressants/
Tricyclic antidepressants may enhance the effects of oral anticoagulants. /Tricyclic Antidepressants/
A particularly serious but rare drug interaction has been reported when taking monoamine oxidase inhibitors and tricyclic antidepressants concomitantly. /Tricyclic Antidepressants/
This product is also contraindicated in patients taking any monoamine oxidase inhibitor antidepressants, such as niramide, isocarboxazid, transcycloprothrombin, or phenelzine. /Hydrochloride/
For more complete data on interactions of protriptyline (32 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 240 mg/kg
Intraperitoneal LD50 in rats: 42 mg/kg
Oral LD50 in mice: 269 mg/kg
Intraperitoneal LD50 in mice: 67 mg/kg
For more complete data on non-human toxicity values of protriptyline (8 types), 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 carbon-tricyclic compound with antidepressant effects. It is derived from the hydride of dibenzo[a,d][7]annulene. Protriptyline hydrochloride is a dibenzocyclohepten derivative tricyclic antidepressant (TCA). TCAs have a structure similar to phenothiazine drugs, containing a tricyclic ring system with an alkylamine substituent attached to the central ring. In non-depressed patients, protriptyline does not affect mood or arousal but may cause sedation. In depressive patients, protriptyline has a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. Furthermore, long-term use of TCAs downregulates cortical β-adrenergic receptors and sensitizes postsynaptic serotonergic receptors. The antidepressant effect of tricyclic antidepressants (TCAs) is thought to be due to an overall enhancement of serotonergic neurotransmission. TCAs can also block histamine H1 receptors, α1-adrenergic receptors, and muscarinic receptors, resulting in their sedative, hypotensive, and anticholinergic effects (e.g., blurred vision, dry mouth, constipation, urinary retention), respectively. For a complete list of side effects, please see the Toxicity section below. Protriptyline is used to treat depression. Protriptyline is a tricyclic antidepressant. Protriptyline is a tricyclic antidepressant that has been widely used to treat major depressive disorder. Most tricyclic antidepressants have been shown to cause a low incidence of mild, transient elevations in serum enzymes, and rare, clinically significant acute cholestatic liver injury. However, the potential hepatotoxicity of protriptyline has not been fully elucidated. Protriptyline hydrochloride is a dibenzocyclohepten derivative tricyclic antidepressant (TCA). TCAs have a structure similar to phenothiazines, both containing a tricyclic ring system with an alkylamine substituent attached to the central ring. In non-depressive patients, protriptyline does not affect mood or arousal but may cause sedation. Protriptyline has a positive effect on mood in patients with depression. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. Furthermore, long-term use of TCAs downregulates cortical β-adrenergic receptors and sensitizes postsynaptic serotonergic receptors. The antidepressant effect of TCAs is thought to be due to an overall enhancement of serotonergic neurotransmission. Tricyclic antidepressants (TCAs) also block histamine H1 receptors, α1-adrenergic receptors, and muscarinic receptors, resulting in their sedative, hypotensive, and anticholinergic effects (e.g., blurred vision, dry mouth, constipation, urinary retention), respectively. For a complete list of side effects, see the Toxicity section below. Protriptyline can be used to treat depression.
Tricyclic antidepressants, with effects and side effects similar to imipramine.
It may cause excitement.
See also: Protriptyline hydrochloride (salt form).
Drug Indications
For the treatment of depression.

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Mechanism of Action
Protriptyline works by reducing the reuptake of norepinephrine and serotonin (5-HT).
The effects of tricyclic antidepressants on the metabolism of catecholamines and indoleamines in the brain have made significant contributions to the "bioamine hypothesis" of depression. ……/All/Blocks the reuptake of norepinephrine at adrenergic nerve endings. /Demethylated analogs are more potent in this action/ /Tricyclic antidepressants/

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Therapeutic Uses
Adrenergic reuptake inhibitors; antidepressants, tricyclic
Tricyclic (dibenzocyclohepten) antidepressants can be used to treat endogenous and exogenous depression. It also enhances psychomotor activity; this property enhances its use in patients with withdrawal and incapacity. Hydrochloride salts may be particularly suitable for treating patients with depression whose main symptoms are psychomotor retardation, apathy, and fatigue… Hydrochloride salts have a sedative effect. ...May be suitable for initial treatment of sleep disorders and depression...The medication does reduce the number of awakenings, increase stage IV sleep, and significantly reduce REM sleep time. /Tricyclic antidepressants/
For more complete data on the therapeutic uses of protriptyline (of 8 types), please visit the HSDB record page.

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Drug Warnings
...Has anticholinergic properties and therefore should not be used in patients with pyloric obstruction, glaucoma, or urinary retention. /Hydrochloride/
...Those with symptoms of agitation, anxiety, and tension often become more agitated after using protriptyline.
This medication may exacerbate anxiety and should not be used in patients with anxiety and depression unless concomitant with sedatives (such as phenothiazines with sedative effects...or more conventional sedatives). /Hydrochloride/
The incidence of tachycardia and orthostatic hypotension...is higher than with other antidepressants; therefore, patients with cardiovascular disease and elderly patients should be closely monitored for these adverse reactions. /Hydrochloride/
For more complete data on drug warnings for protriptyline (28 in total), please visit the HSDB records page.

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Pharmacodynamics
Protriptyline is a tricyclic antidepressant. The mechanism of action of tricyclic antidepressants is believed to be the inhibition of the reuptake of neurotransmitters such as norepinephrine and serotonin by nerve cells. Following the recommended dosing regimen, the effects of antidepressants typically appear after two weeks. Gradual changes occur in the cerebral cortex and hippocampus (as part of the limbic system, involved in mood regulation) as receptor sensitivity increases. While α1 and β1 receptors are sensitized, α2 receptors are desensitized (leading to increased norepinephrine production). Tricyclic antidepressants have also been reported to alter pain perception, including neuropathic pain or neuralgia, and therefore may have an analgesic effect. The mechanism of this analgesic effect is not fully elucidated; however, it is thought to involve the regulation of the endogenous opioid system in the central nervous system through an indirect serotonergic pathway. Tricyclic antidepressants are also effective in preventing migraines, but they cannot stop acute migraine attacks, which may be related to 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.)