Chemistry:Estianeptine

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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

The drug is the (S)- enantiomer of the atypical 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

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

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Estianeptine - Tonix Pharmaceuticals Holding Corp - AdisInsight". https://adisinsight.springer.com/drugs/800073998?error=cookies_not_supported&code=5bf5445f-88ac-47e1-af3d-66c5fbe020cb. 
  2. ↑ 2.0 2.1 2.2 2.3 "Delving into the Latest Updates on Estianeptine with Synapse". 8 May 2025. https://synapse.patsnap.com/drug/fd61f77ee56a4cbcb62becbab7a2b9c0. 
  3. ↑ "Estianeptine Drug Profile". 1 January 1900. https://pryzm.ozmosi.com/product/30520. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "Proposed Mechanism of Tianeptine, a Plastogen Antidepressant in Phase II Development in the United States". CNS Summit 2023. 20. Boston, Massachusetts, US: Innovations in Clinical Neuroscience. 8 November 2023. pp. S23–S23. https://pmc.ncbi.nlm.nih.gov/articles/PMC10712291/pdf/icns_20_10-12_s1.pdf#page=17. Retrieved 4 August 2026. 
  5. ↑ 5.0 5.1 "Tianeptine: enantiomeric separations, structural assignment, and biological interactions". Talanta 294. November 2025. doi:10.1016/j.talanta.2025.128197. PMID 40339337. 
  6. ↑ "Classics in Chemical Neuroscience: Tianeptine". ACS Chemical Neuroscience 15 (21): 3863–3873. November 2024. doi:10.1021/acschemneuro.4c00519. PMID 39382192. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "A Randomized Placebo-Controlled Multicenter Trial of Monotherapy with TNX-601 ER (Tianeptine Hemioxalate Extended-Release Tablets) for Treatment of Major Depressive Disorder (MDD)". American Society of Clinical Psychopharmacology (ASCP) 2023 Annual Meeting. Miami, Florida. 1 June 2023. https://www.tonixpharma.com/wp-content/uploads/2023/06/ASCP-Poster-2023-A-Randomized-Placebo-Controlled-Multicenter-Trial-of-Monotherapy-with-TNX-601-ER.pdf. 
  8. ↑ BioWorld (25 July 2023). "Rat NOR test results support memory- and cognition-enhancing effects of estianeptine". https://www.bioworld.com/articles/699319-rat-nor-test-results-support-memory-and-cognition-enhancing-effects-of-estianeptine. 
  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". 24 July 2023. https://ir.tonixpharma.com/news-events/press-releases/detail/1406/tonix-pharmaceuticals-announces-data-supporting-the-memory. 
  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". 17 May 2023. https://ir.tonixpharma.com/news-events/press-releases/detail/1389/tonix-pharmaceuticals-announces-pharmacology-and-medicinal. 
  11. ↑ "Effects of the (+) and (-) enantiomers of the antidepressant drug tianeptine on 5-HTP-induced behaviour". Neuropharmacology 36 (3): 383–387. March 1997. doi:10.1016/s0028-3908(97)00016-6. PMID 9175617. 
  12. ↑ "Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists". International Journal of Molecular Sciences 23 (17). September 2022. doi:10.3390/ijms231710070. 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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