Tianeptinaline
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| Drug class | Histone deacetylase inhibitor; Cognitive enhancer |
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| Formula | C27H31ClN4O3S |
| Molar mass | 527.08 g·mol−1 |
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Tianeptinaline is a histone deacetylase (HDAC) inhibitor which was derived via structural modification of the tricyclic antidepressant (TCA) tianeptine.[1][2][3][4]
| Enzyme | IC50 (nM) |
|---|---|
| HDAC1 | 240 |
| HDAC2 | 120 |
| HDAC3 | 155 |
| HDAC4 | ND |
| HDAC5 | >80,000 |
| HDAC6 | >80,000 |
| HDAC7 | ND |
| HDAC8 | ND |
| HDAC9 | ND |
| Refs: [4] | |
It potently inhibits the class I HDAC1, HDAC2, and HDAC3 with IC50 values of 240 nM, 120 nM, and 155 nM, whereas it did not inhibit the class II HDAC5 or HDAC6 (IC50 = >80,000 nM).[1][4] Potential actions against other HDACs, such as HDAC4, HDAC7, HDAC8, and HDAC9, were not described.[4] The drug has been found to enhance CREB-mediated transcription, penetrate into the brain, and enhance contextual fear conditioning, a behavioral measure of hippocampus-dependent memory, in rodents.[2][4]
The chemical synthesis of tianeptinaline has been described.[4] Another analogue of tianeptinaline, known as tianeptinostat, is also a potent HDAC inhibitor.[1][4] However, whereas tianeptinaline did not inhibit HDAC6, tianeptinostat was a highly potent inhibitor of HDAC6 in addition to the class I HDACs.[4]
Tianeptinaline and tianeptinostat were first described in the scientific literature by 2018.[1][4] They were derived from tianeptine after it was noted that tianeptine has a similar chemical structure to that of the potent clinically used HDAC inhibitor vorinostat (SAHA) and that tianeptine itself is a weak HDAC inhibitor (IC50 = 25,000 nM, 82,000 nM, and >2 mM at HDAC1, HDAC2, and HDAC3, respectively).[1][3][4]
See also
[edit]References
[edit]- 1 2 3 4 5 Rodrigues DA, Pinheiro PS, Sagrillo FS, Bolognesi ML, Fraga CA (November 2020). "Histone deacetylases as targets for the treatment of neurodegenerative disorders: Challenges and future opportunities". Medicinal Research Reviews. 40 (6): 2177–2211. doi:10.1002/med.21701. PMID 32588916.
The work developed by Zhao et al50 describes the design of new HDACis based structurally on the tricyclic antidepressant tianeptine (1). Since tianeptine's (1) structure resembles the known pharmacophoric model for HDAC inhibition (cap‐linker‐zinc binder group), the authors decided to make the hybridization between tianeptine (1) and SAHA (2) or CI‐994 (3), resulting in new chemical entities with replacements at the carboxylic acid moiety of tianeptine by hydroxamic acid (4) and ortho‐aminoanilide (5) (Figure 5). Comparing the HDAC inhibition data, tianeptine (1) itself is a weak HDACi, with potency (HDAC1 IC50 = 82 µM, HDAC2 IC50 = 25 µM, HDAC3 IC50 > 2 mM)50 comparable to that of other carboxylic acids, such as valproic acid. [...] The substitution by the hydroxamic acid resulted in a pan‐HDAC inhibition profile for tianeptinostat (4) (HDAC1 IC50 = 0.028 µM, HDAC2 IC50 = 0.033 µM, HDAC3 IC50 = 0.051 µM, HDAC5 IC50 > 80 µM, HDAC6 IC50 = 0.0016 µM), similar to the profile of SAHA (2) (HDAC1 IC50 = 0.007 µM, HDAC2 IC50 = 0.010 µM, HDAC3 IC50 = 0.021 µM, HDAC5 IC50 > 80 µM, HDAC6 IC50 = 0.0012 µM), while the substitution by the ortho‐aminoanilide moiety resulted in the class I selective inhibitor tianeptinaline (5) (HDAC1 IC50 = 0.240 µM, HDAC2 IC50 = 0.120 µM, HDAC3 IC50 = 0.155 µM, HDAC5 IC50 > 80 µM, HDAC6 IC50 > 80 µM), such as CI‐994 (3) (HDAC1 IC50 = 0.145 µM, HDAC2 IC50 = 0.115 µM, HDAC3 IC50 = 0.124 µM, HDAC5 IC50 > 80 µM, HDAC6 IC50 > 80 µM).50 [...]
- 1 2 Sharma R, Sharma S, Thakur A, Singh A, Singh J, Nepali K, et al. (2022). "The Role of Epigenetic Mechanisms in Autoimmune, Neurodegenerative, Cardiovascular, and Imprinting Disorders". Mini Reviews in Medicinal Chemistry. 22 (15): 1977–2011. doi:10.2174/1389557522666220217103441. PMID 35176978.
Zhao et al. synthesized new HDAC inhibitors structurally based on tianeptine, a drug mainly used for the treatment of Major Depressive Disorder (MDD). Resultantly, tianeptinaline (38) was identified that demonstrated amplified potency and selectivity among the HDAC family. In in vitro studies, tianeptinaline elevated histone acetylation (EC50 = 3.98 µM) and increased cAMP response element binding protein (CREB), facilitating transcription and expression of Arc (activity-regulated cytoskeleton associated protein). Tianeptinaline increased contextual fear conditions and demonstrated better brain penetration than tianeptine. In light of the evidenced results, tianeptinaline appears to be a promising pharmacological tool for the treatment of chromatin mediated neuroplasticity, impairment of memory and learning disorder, and central nervous system diseases (Fig. 4) [112].
- 1 2 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.
Structurally, the tianeptine scaffold is conducive to creative medicinal chemistry, and the pharmacology of new synthetic analogs remains a fascinating prospect (recently, structural analogs of tianeptine have been reported as class I histone deacetylase (HDAC) inhibitors).118
- 1 2 3 4 5 6 7 8 9 10 Zhao WN, Ghosh B, Tyler M, Lalonde J, Joseph NF, Kosaric N, et al. (September 2018). "Class I Histone Deacetylase Inhibition by Tianeptinaline Modulates Neuroplasticity and Enhances Memory" (PDF). ACS Chemical Neuroscience. 9 (9): 2262–2273. doi:10.1021/acschemneuro.8b00116. PMID 29932631.