μ Opioid Receptor (MOR); δ Opioid Receptor (DOR)
Tianeptine targets multiple receptors and pathways. It acts as a selective facilitator of 5-HT uptake in vitro and in vivo, enhancing serotonin reuptake into presynaptic neurons. It has no affinity for a wide range of receptors, including 5-HT and dopamine (IC₅₀ > 10 μM), and has no effect on noradrenalin or dopamine uptake. Recent studies have shown that tianeptine is a complete agonist of the μ-opioid receptor (MOR). It also modulates the D2 and D3 dopamine receptors and acts on NMDA and AMPA receptors. Its inhibition of MMP-9 through the PI3K/Akt-mediated NF-kappaB pathway suggests anti-inflammatory effects. This multi-targeted mechanism may contribute to its antidepressant and anxiolytic effects.

In vitro, Tianeptine is a selective facilitator of 5-HT uptake. It has no affinity for a wide range of receptors, including 5-HT and dopamine (IC₅₀ > 10 μM) and has no effect on noradrenalin or dopamine uptake. It inhibits MMP-9 by suppressing the PI3K/Akt-mediated NF-kappaB pathway. Its activity is typically assessed by measuring its effects on serotonin reuptake in synaptosomal preparations or cell lines expressing the serotonin transporter. The compound's lack of affinity for various receptors confirms its unique mechanism of action. However, detailed in vitro potency data for its various activities are not extensively documented.

In vivo, Tianeptine is an effective antidepressant used to alleviate symptoms of depression and anxiety. It enhances serotonin reuptake in vivo. Its mechanism of action differs from SSRIs and supports the hypothesis that its effects are related to altered glutamatergic activity in the amygdala and hippocampus. As a complete agonist of the μ-opioid receptor, it may also have effects on pain pathways. The compound's lack of sedative effects makes it a favorable option for some patients. It has also been studied for asthma and irritable bowel syndrome. Clinical use has established its efficacy and safety profile.

In vitro non-cell enzyme/receptor binding assays for Tianeptine typically involve measuring its binding affinity to the serotonin transporter and various receptors using radioligand binding studies. Membrane preparations from cells expressing the serotonin transporter or other receptors are incubated with the compound and a radiolabeled ligand. The displacement of the radiolabeled ligand is measured to determine the compound's affinity (Ki). Functional assays, such as measuring serotonin uptake inhibition, are used to determine its activity as a serotonin reuptake enhancer. These assays provide quantitative data on the compound's interactions with its molecular targets.

In vitro cell-based assays for Tianeptine use neuronal cell lines or synaptosomal preparations to study its effects on serotonin reuptake. Cells are treated with the compound, and the uptake of radiolabeled serotonin is measured. Its effects on dopamine and noradrenalin uptake can also be assessed. The compound's effects on MMP-9 expression can be studied in cells stimulated with inflammatory stimuli, and MMP-9 levels are measured by ELISA or zymography. Its effects on cell viability and proliferation can be assessed using MTT or similar assays. These studies help to characterize the compound's cellular mechanism of action.

In vivo animal studies for Tianeptine employ models of depression, such as the forced swim test or tail suspension test in rodents. The compound is administered orally or intraperitoneally, and its ability to reduce immobility time is measured. Its effects on anxiety can be assessed using the elevated plus maze or open field test. Its effects on neurotransmitter levels in the brain can be measured by microdialysis. Its anti-inflammatory effects can be studied in models of inflammation. Pharmacokinetic studies in these models provide information about the compound's absorption, distribution, metabolism, and excretion.

Absorption, Distribution and Excretion
Absorbed well, with a bioavailability of approximately 99%. Excreted bile as a glucuronide and glutamine conjugate. 0.8 L/kg (0.77 +/- 0.31 L/kg) Rapidly cleared by the kidneys. Metabolism/Metabolites Tineptetin is primarily metabolized via β-oxidation of its heptanoic acid side chain. Metabolism was investigated in healthy male volunteers following a single oral administration of a radioisotope (¹⁴C) labeled tianeptetin compound. After 1 week, approximately 66% of the dose was excreted by the kidneys (55% within the first 24 hours). After 24 hours, 3% of the drug was detected in the urine as excreted unchanged. β-oxidation of tianeptetin produces three major metabolites. The metabolite profiles of tianeptetin in feces and plasma are similar in nature to those in urine.

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Biological half-life
Approximately 2.5 hours

Tianeptine has a molecular weight of 436.95 g/mol and a molecular formula of C₂₁H₂₅ClN₂O₄S. It is classified as a selective serotonin reuptake enhancer (SSRE). The compound is typically administered orally and is well-absorbed. It has a half-life of approximately 2.5 hours and is primarily metabolized in the liver by beta-oxidation and demethylation. It is excreted primarily in the urine. Its pharmacokinetic profile supports its use as a twice-daily or three-times-daily medication. The compound should be stored under appropriate conditions to maintain its stability.

Protein binding
95% binds to plasma proteins.
Tianeptine is generally well-tolerated, with a safety profile established through clinical use. Common side effects include gastrointestinal disturbances, such as nausea and abdominal pain, as well as dizziness and headache. It is contraindicated in patients with a history of hypersensitivity to Tianeptine or any of its components. Its use during pregnancy and lactation is not recommended due to insufficient safety data. The compound's lack of sedative effects and low potential for dependence make it a favorable option for some patients. However, its μ-opioid receptor agonist activity suggests potential for abuse and dependence, which has led to regulatory restrictions in some countries.

Neuropharmacology.2006 Jun;50(7):824-33;Stress.2006 Mar;9(1):29-40.

Tianeptine is a racemic mixture composed of equimolar amounts of (R)-thiapontine and (S)-thiapontine. It is an atypical antidepressant used in Europe to treat patients who do not respond well to selective serotonin reuptake inhibitors (SSRIs). It has effects as a μ-opioid receptor agonist, a second-generation antipsychotic, and an anxiolytic. It contains (R)-thiapontine and (S)-thiapontine. Tianeptine is primarily used to treat major depressive disorder and has also been investigated for the treatment of irritable bowel syndrome (IBS). Structurally, it belongs to the tricyclic antidepressant class (TCA), but its pharmacological properties differ from typical tricyclic antidepressants. Tianeptine was discovered and patented by the French Medical Research Association in the 1960s. Currently, thiapontine is approved in France and manufactured and marketed by Laboratories Servier SA. This drug is marketed under the brand name \"Coaxil\" in several other European countries, and under the brand names \"Stablon\" and \"Tatinol\" in Asia (including Singapore) and Latin America, but is not marketed in Australia, Canada, New Zealand, the United Kingdom, or the United States. Drug Indications Primarily used to treat major depressive disorder and anxiety. Its efficacy in treating fibromyalgia pain is currently under investigation. Mechanism of Action Recent studies have shown that tianeptine is a complete agonist of the μ-opioid receptor (MOR). The μ-opioid receptor is currently being investigated as an effective target for antidepressant treatment. The clinical efficacy of tianeptine is believed to be attributed to its regulatory effects on these receptors. In addition to its effects on opioid receptors, previous studies have suggested that tianeptine's effects are related to its influence on serotonin receptors, dopamine (D2/3) receptors, and glutamate receptors, as described below: tianeptine challenges the monoaminergic hypothesis of depression, as well as the widely accepted monoaminergic mechanism upon which most known antidepressant mechanisms of action are based. Specifically, this drug is believed to persistently alter the burst firing of glutamate receptors at the CA3 synapse in the hippocampus. Current research indicates that tianeptine exerts its antidepressant effects by modulating glutamate receptor activity (e.g., AMPA and NMDA receptors) and influencing the release of brain-derived neurotrophic factor (BDNF), thereby affecting neuroplasticity. More recent research supports the role of tianeptine in modulating glutamatergic activity in the amygdala (a brain region associated with memory and emotion). Tianeptine reduces the hypothalamic-pituitary-adrenal (HPA) axis response to stress, thus preventing stress-related behavioral problems. In rodents, acute restraint stress increases extracellular glutamate levels in the basolateral amygdala, an effect that tianeptine inhibits. Interestingly, the selective serotonin reuptake inhibitor (SSRI) fluoxetine increases extracellular glutamate levels in the basolateral amygdala under all stress conditions. These data suggest that tianeptine's mechanism of action differs from SSRIs and support the hypothesis that its mechanism of action is related to altered glutamatergic activity in the amygdala and hippocampus. In addition to the above mechanisms, tianeptine is a unique antidepressant and anti-anxiety drug that stimulates the uptake of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in brain tissue. Although monoamine neurotransmitters serotonin (5-HT), norepinephrine (NA), and dopamine (DA) have been shown to be associated with the development of depression, it is currently recognized that monoamine deficiency is insufficient to explain the mechanism of action of antidepressants. Large-scale epidemiological analyses show that anxiety disorders and major depressive disorder are commonly comorbid. This makes antidepressants with anti-anxiety properties particularly unique and attractive. Tianeptine effectively reduces depressive symptoms in mild to severe major depressive disorder and relieves anxiety symptoms associated with depression without the need for combination with anti-anxiety medications. However, these findings are also controversial. In a study of healthy volunteers, subjects receiving tianeptine showed lower accuracy in recognizing facial expressions, indicating that psychomotor symptoms of depression were not being improved. The tianeptine group also exhibited memory decline and reduced attentional alertness to various stimuli.
Tianeptine (Stablon, Coaxil) is an atypical antidepressant with a unique mechanism of action as a selective serotonin reuptake enhancer (SSRE). It is also a complete agonist of the μ-opioid receptor (MOR). The compound enhances serotonin reuptake and modulates dopamine receptors, NMDA, and AMPA receptors. It inhibits MMP-9 through the PI3K/Akt-mediated NF-kappaB pathway. Tianeptine is used to alleviate symptoms of depression and anxiety without causing sedative effects. It has also been studied for asthma and irritable bowel syndrome. Not approved for use in all countries; subject to regulatory restrictions in some regions.

C21H25CLN2O4S

436.9522

436.122

72797-41-2

72797-41-2;30123-17-2 (sodium);

68870

White to off-white solid powder

1.38±0.1 g/cm3(Predicted)

609.2±65.0 °C(Predicted)

129-131℃

5.729

2

6

8

29

654

0

ClC1C([H])=C([H])C2=C(C=1[H])S(N(C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1C2([H])N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(=O)O[H])(=O)=O

JICJBGPOMZQUBB-UHFFFAOYSA-N

InChI=1S/C21H25ClN2O4S/c1-24-18-9-6-5-8-16(18)21(23-13-7-3-2-4-10-20(25)26)17-12-11-15(22)14-19(17)29(24,27)28/h5-6,8-9,11-12,14,21,23H,2-4,7,10,13H2,1H3,(H,25,26)

7-[(3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][2,1]benzothiazepin-11-yl)amino]heptanoic acid

Tianeptine; 72797-41-2; Stablon; Tianeptina; 7-[(3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][2,1]benzothiazepin-11-yl)amino]heptanoic acid;

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.)