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Estianeptine

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Estianeptine
Clinical data
Other names(S)-Tianeptine; S-Tianeptine; TNX-4300; TNX4300
Routes of
administration		Oral[1]
Drug classPeroxisome proliferator-activated receptor (PPAR) agonist; PPARβ/δ and PPARγ agonist
Identifiers
  • 7-[[(11S)-3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][2,1]benzothiazepin-11-yl]amino]heptanoic acid
PubChem CID
ChemSpider
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H25ClN2O4S
Molar mass436.95 g·mol−1
3D model (JSmol)
  • CN1C2=CC=CC=C2[C@@H](C3=C(S1(=O)=O)C=C(C=C3)Cl)NCCCCCCC(=O)O
  • 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)/t21-/m0/s1
  • Key:JICJBGPOMZQUBB-NRFANRHFSA-N

Estianeptine, also known as (S)-tianeptine and by its developmental code name TNX-4300, is a peroxisome proliferator-activated receptor (PPAR) agonist and atypical tricyclic antidepressant (TCA) which is under development for the treatment of Alzheimer's disease, bipolar disorders, major depressive disorder, and Parkinson's disease.[1][2][3][4][5] It is taken orally.[1]

Pharmacology

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Estianeptine is the (S)- enantiomer of the atypical tricyclic antidepressant (TCA) and weak opioid tianeptine.[1][4][5][6] It acts as a selective PPARβ/δ and PPARγ agonist.[1][2][4][7] The drug has been found to promote neuroplasticity in vitro, which is thought to be mediated by its PPAR agonism.[4][7] In addition, it has been found to improve cognition and memory in rodents.[8][9] In contrast to tianeptine and (R)-tianeptine, estianeptine shows no activity as a μ-opioid receptor (MOR) agonist.[1][4][7] Moreover, unlike estianeptine, (R)-tianeptine has no activity as a PPAR agonist.[4][7] It has been proposed that estianeptine, via its PPAR agonism, is responsible for the antidepressant effects of tianeptine, rather than tianeptine's weak MOR agonism that manifests at high doses being responsible.[4][7][10] Tianeptine's PPAR agonism may also be responsible for the drug's anti-inflammatory effects.[7]

History

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Estianeptine was first described in the scientific literature by 1997.[11] It is being developed by Tonix Pharmaceuticals.[1][2][4] As of August 2023, the drug is in the preclinical research stage of development for all indications.[1][2] Tianeptine's PPAR agonism was first described in 2022.[12]

See also

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References

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  1. 1 2 3 4 5 6 7 8 "Estianeptine - Tonix Pharmaceuticals Holding Corp - AdisInsight". adisinsight.springer.com. Retrieved 4 August 2026.
  2. 1 2 3 4 "Delving into the Latest Updates on Estianeptine with Synapse". Synapse. 8 May 2025. Retrieved 4 August 2026.
  3. ↑ "Estianeptine Drug Profile". Ozmosi. 1 January 1900. Retrieved 4 August 2026.
  4. 1 2 3 4 5 6 7 8 Sullivan GM, Daugherty BL, Hsu DT, Rideout DC, Bavari S, Cho J, et al. (8 November 2023). Proposed Mechanism of Tianeptine, a Plastogen Antidepressant in Phase II Development in the United States. CNS Summit 2023. Vol. 20. Boston, Massachusetts, US: Innovations in Clinical Neuroscience. pp. S23. PMC 10712291.
  5. 1 2 Aslani S, Nafie J, Wahab MF, Armstrong DW (November 2025). "Tianeptine: enantiomeric separations, structural assignment, and biological interactions". Talanta. 294 128197. doi:10.1016/j.talanta.2025.128197. PMID 40339337.
  6. ↑ Nishio Y, Lindsley CW, Bender AM (November 2024). "Classics in Chemical Neuroscience: Tianeptine". ACS Chemical Neuroscience. 15 (21): 3863–3873. doi:10.1021/acschemneuro.4c00519. PMC 11587517. PMID 39382192.
  7. 1 2 3 4 5 6 Sullivan GM, Peters A, Hsu D, Rideout D, Roush T, Daugherty B, et al. (1 June 2023). A Randomized Placebo-Controlled Multicenter Trial of Monotherapy with TNX-601 ER (Tianeptine Hemioxalate Extended-Release Tablets) for Treatment of Major Depressive Disorder (MDD) (PDF). American Society of Clinical Psychopharmacology (ASCP) 2023 Annual Meeting. Miami, Florida.
  8. ↑ BioWorld (25 July 2023). "Rat NOR test results support memory- and cognition-enhancing effects of estianeptine". BioWorld. Retrieved 4 August 2026.
  9. ↑ "Tonix Pharmaceuticals Announces Data Supporting the Memory- and Cognition-Enhancing Effects of Racemic Tianeptine and (S)-Tianeptine, but not (R)-Tianeptine, in the In Vivo Rat Novel Object Recognition (NOR) Test". Tonix Pharmaceuticals Holding Corp. 24 July 2023. Retrieved 4 August 2026.
  10. ↑ "Tonix Pharmaceuticals Announces Pharmacology and Medicinal Chemistry Results that Reveal the Molecular Mechanism of Action of Tianeptine, the Active Ingredient of TNX-601 ER, in Treating Depression". Tonix Pharmaceuticals Holding Corp. 17 May 2023. Retrieved 4 August 2026.
  11. ↑ Oluyomi AO, Datla KP, Curzon G (March 1997). "Effects of the (+) and (-) enantiomers of the antidepressant drug tianeptine on 5-HTP-induced behaviour". Neuropharmacology. 36 (3): 383–387. doi:10.1016/s0028-3908(97)00016-6. PMID 9175617.
  12. ↑ Helmstädter M, Schierle S, Isigkeit L, Proschak E, Marschner JA, Merk D (September 2022). "Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists". International Journal of Molecular Sciences. 23 (17) 10070. doi:10.3390/ijms231710070. PMC 9456086. PMID 36077469. Table 1. In vitro activity of FAMs with possibly relevant side-target activity and with potential for SOSA1. [...] Tianeptine: [...] partial PPARδ agonist EC50 = 28 ± 4 µM (43 ± 4% max. act.)
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