TAK-653

Short description: Experimental antidepressant

TAK-653

Legal status
Legal status|

* Investigational

Identifiers

IUPAC name

* 9-[4-(Cyclohexyloxy)phenyl]-7-methyl-3H,4H-2λ6-pyrazino[2,1-c][1,2,4]thiadiazine-2,2-dione

CAS Number|

* 1358751-06-0

DrugBank|

* DB16304

UNII|

* 9E3TOE5RIZ

Chemical and physical data
Formula| C19H23N3O3S
Molar mass| 373.47 g·mol−1

TAK-653 is an experimental drug being investigated as a treatment for treatment-resistant depression. It is being developed by Takeda Pharmaceuticals (Millennium Pharmaceuticals, Inc.).[1]

## Mechanism of action

TAK-653 is a selective positive allosteric modulator (PAM) of the AMPA receptor.[2][3] TAK-653 and other AMPA PAMs potentiate the effects of agonists at the main site of the AMPA receptor by slowing the rate of desensitization and internalization of the receptor.[4]

## Antidepressant research

There is evidence suggesting that activation of the AMPA receptor, downstream activation of mTOR, and upregulation of BDNF are central to the antidepressant effects of certain NMDA receptor antagonists such as ketamine.[5] Blockage of the AMPA receptor nullifies the anti-depressant action of ketamine.[6] By potentiating the effect of endogenous glutamate at the AMPA receptor, TAK-653 more directly influences AMPA receptor-mediated transcription.[4]

The potential use of TAK-653 as a non-psychotomimetic antidepressant is cited as reason for its investigation.[2] Initial research found that TAK-653, unlike ketamine, did not induce hyperlocomoter responses in rats. However, a later human trial investigating the CNS stimulatory properties and tolerability of TAK-653 reported that although the CNS stimulatory properties of the drug were less pronounced than other psychostimulants, TAK-653 did appear to possess at least some stimulant-like effects.[3] No severe adverse effects were noted in the trial.[3]

AMPA receptor agonists are likely not viable for clinical applications as they present a risk of inducing seizures and overexcitation-induced neurotoxicity at doses close to their therapeutic window.[7][8][9] TAK-653 possesses minimal direct AMPA agonist properties.[7] TAK-653 provides a 419 fold safety margin against convulsions relative to therapeutic doses in rats.[7]

## References

1. ↑ Millennium Pharmaceuticals, Inc. (2018-02-20). "A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of TAK-653 in the Treatment of Subjects With Treatment-Resistant Depression". https://clinicaltrials.gov/ct2/show/NCT03312894.
2. ↑ 2.0 2.1 "TAK-653, an AMPA receptor potentiator with minimal agonistic activity, produces an antidepressant-like effect with a favorable safety profile in rats". Pharmacology, Biochemistry, and Behavior 211: 173289. December 2021. doi:10.1016/j.pbb.2021.173289. PMID 34655652.
3. ↑ 3.0 3.1 3.2 "Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers". Translational Psychiatry 12 (1): 408. September 2022. doi:10.1038/s41398-022-02148-w. PMID 36153330.
4. ↑ 4.0 4.1 "Stargazin controls the pharmacology of AMPA receptor potentiators". Proceedings of the National Academy of Sciences of the United States of America 103 (26): 10064–10067. June 2006. doi:10.1073/pnas.0603128103. PMID 16785437. Bibcode: 2006PNAS..10310064T.
5. ↑ "Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex". European Psychiatry 29 (7): 419–423. September 2014. doi:10.1016/j.eurpsy.2013.10.005. PMID 24321772.
6. ↑ "Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism". Journal of Psychiatry & Neuroscience 42 (4): 222–229. June 2017. doi:10.1503/jpn.160175. PMID 28234212.
7. ↑ 7.0 7.1 7.2 "Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement". Scientific Reports 11 (1): 14532. July 2021. doi:10.1038/s41598-021-93888-0. PMID 34267258. Bibcode: 2021NatSR..1114532S.
8. ↑ "AMPA receptors as a molecular target in epilepsy therapy". Acta Neurologica Scandinavica. Supplementum 127 (197): 9–18. 2013. doi:10.1111/ane.12099. PMID 23480151.
9. ↑ "Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors". Biomolecules 10 (3): 464. March 2020. doi:10.3390/biom10030464. PMID 32197322.

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