View source for Osavampator

{{Short description|Experimental antidepressant}}
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{{Infobox drug
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| image = TAK-653.svg
| width = 175px
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| legal_status = Investigational
<!-- Pharmacokinetic data -->| bioavailability =
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| elimination_half-life = 33.1–47.8 hours
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| CAS_number = 1358751-06-0
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| PubChem = 56655833
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| DrugBank_Ref =
| DrugBank = DB16304
| ChemSpiderID_Ref =
| ChemSpiderID = 81367230
| UNII = 9E3TOE5RIZ
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| ChEMBL = 4594403
| synonyms = TAK-653; NBI-1065845; NBI-845
<!-- Chemical data -->| IUPAC_name = 9-(4-cyclohexyloxyphenyl)-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide
| C = 19
| H = 23
| N = 3
| O = 3
| S = 1
| SMILES = CC1=CN2CCS(=O)(=O)N=C2C(=N1)C3=CC=C(C=C3)OC4CCCCC4
| StdInChI_Ref =
| StdInChI = 1S/C19H23N3O3S/c1-14-13-22-11-12-26(23,24)21-19(22)18(20-14)15-7-9-17(10-8-15)25-16-5-3-2-4-6-16/h7-10,13,16H,2-6,11-12H2,1H3
| StdInChIKey_Ref =
| StdInChIKey = PXJBHEHFVQVDDS-UHFFFAOYSA-N
}}
'''Osavampator''' (developmental code names '''TAK-653''' and '''NBI-1065845''') is an [[experimental drug]] being investigated as a treatment for [[treatment-resistant depression]].<ref name="AdisInsight-TAK-653">{{cite web | title=TAK 653 | work = AdisInsight | publisher = Springer Nature Switzerland AG | date=5 August 2024 | url=https://adisinsight.springer.com/drugs/800043331 | access-date=9 August 2024}}</ref> It is being developed by [[Takeda Pharmaceutical Company|Takeda Pharmaceuticals]] (Millennium Pharmaceuticals, Inc.).<ref name="AdisInsight-TAK-653" /><ref>{{ClinicalTrialsGov|NCT03312894|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}}</ref>
==Pharmacology==
Osavampator is a [[binding selectivity|selective]] [[positive allosteric modulator]] (PAM) of the [[AMPA receptor]].<ref name=":0">{{cite journal | vauthors = Hara H, Suzuki A, Kunugi A, Tajima Y, Yamada R, Kimura H | title = TAK-653, an AMPA receptor potentiator with minimal agonistic activity, produces an antidepressant-like effect with a favorable safety profile in rats | journal = Pharmacology, Biochemistry, and Behavior | volume = 211 | pages = 173289 | date = December 2021 | pmid = 34655652 | doi = 10.1016/j.pbb.2021.173289 | s2cid = 238754541 | doi-access = free }}</ref><ref name=":1">{{cite journal | vauthors = Dijkstra F, O'Donnell P, Klaassen E, Buhl D, Asgharnejad M, Rosen L, Zuiker R, van Gerven J, Jacobs G | title = 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 | journal = Translational Psychiatry | volume = 12 | issue = 1 | pages = 408 | date = September 2022 | pmid = 36153330 | pmc = 9509332 | doi = 10.1038/s41398-022-02148-w }}</ref> Osavampator and other AMPA PAMs potentiate the effects of [[agonist]]s at the [[orthosteric site|main site]] of the AMPA receptor by slowing the rate of [[downregulation|desensitization and internalization]] of the receptor.<ref name="Tomita 10064–10067">{{cite journal | vauthors = Tomita S, Sekiguchi M, Wada K, Nicoll RA, Bredt DS | title = Stargazin controls the pharmacology of AMPA receptor potentiators | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 26 | pages = 10064–10067 | date = June 2006 | pmid = 16785437 | pmc = 1502506 | doi = 10.1073/pnas.0603128103 | bibcode = 2006PNAS..10310064T | doi-access = free }}</ref>
The terminal [[Biological half-life|half-life]] of osavampator is 33.1–47.8 hours.<ref>{{cite journal | vauthors = Dijkstra F, O'Donnell P, Klaassen E, Buhl D, Asgharnejad M, Rosen L, Zuiker R, van Gerven J, Jacobs G | title = 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 | journal = Translational Psychiatry | volume = 12 | issue = 1 | pages = 408 | date = September 2022 | pmid = 36153330 | pmc = 9509332 | doi = 10.1038/s41398-022-02148-w }}</ref>
==Research==
===Depression===
There is evidence suggesting that activation of the AMPA receptor, downstream activation of [[mammalian target of rapamycin]] (mTOR), and [[upregulation]] of [[brain-derived neurotrophic factor]] (BDNF) are central to the [[antidepressant]] effects of certain [[NMDA receptor antagonist]]s such as [[ketamine]].<ref>{{cite journal | vauthors = Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ | title = Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex | journal = European Psychiatry | volume = 29 | issue = 7 | pages = 419–423 | date = September 2014 | pmid = 24321772 | doi = 10.1016/j.eurpsy.2013.10.005 | s2cid = 23335947 }}</ref> Blockage of the AMPA receptor nullifies the antidepressant actions of ketamine in rodents.<ref name="AleksandrovaPhillipsWang2017">{{cite journal | vauthors = Aleksandrova LR, Phillips AG, Wang YT | title = Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism | journal = Journal of Psychiatry & Neuroscience | volume = 42 | issue = 4 | pages = 222–229 | date = June 2017 | pmid = 28234212 | pmc = 5487269 | doi = 10.1503/jpn.160175 }}</ref> By potentiating the effect of endogenous glutamate at the AMPA receptor, osavampator more directly influences AMPA receptor-mediated transcription.<ref name="Tomita 10064–10067"/>
The potential use of osavampator as a [[hallucinogen|non-psychotomimetic]] antidepressant is cited as reason for its investigation.<ref name=":0" /> Initial research found that osavampator, unlike ketamine, did not induce [[psychostimulant|hyperlocomoter responses]] in rats. However, a later human trial investigating the central nervous system (CNS) stimulatory properties and tolerability of osavampator reported that although the CNS stimulatory properties of the drug were less pronounced than other psychostimulants, osavampator did appear to possess at least some stimulant-like effects.<ref name=":1" /> No severe adverse effects were noted in the trial.<ref name=":1" />
[[AMPA receptor#Agonists|AMPA receptor agonists]] are likely not viable for clinical applications as they present a risk of inducing [[seizure]]s and [[excitotoxicity|overexcitation-induced neurotoxicity]] at doses close to their therapeutic window.<ref name=":2">{{cite journal | vauthors = Suzuki A, Kunugi A, Tajima Y, Suzuki N, Suzuki M, Toyofuku M, Kuno H, Sogabe S, Kosugi Y, Awasaki Y, Kaku T, Kimura H | title = Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement | journal = Scientific Reports | volume = 11 | issue = 1 | pages = 14532 | date = July 2021 | pmid = 34267258 | pmc = 8282797 | doi = 10.1038/s41598-021-93888-0 | bibcode = 2021NatSR..1114532S }}</ref><ref>{{cite journal | vauthors = Rogawski MA | title = AMPA receptors as a molecular target in epilepsy therapy | journal = Acta Neurologica Scandinavica. Supplementum | volume = 127 | issue = 197 | pages = 9–18 | date = 2013 | pmid = 23480151 | pmc = 4506648 | doi = 10.1111/ane.12099 }}</ref><ref>{{cite journal | vauthors = Hanada T | title = Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors | journal = Biomolecules | volume = 10 | issue = 3 | pages = 464 | date = March 2020 | pmid = 32197322 | pmc = 7175173 | doi = 10.3390/biom10030464 | doi-access = free }}</ref> Osavampator possesses minimal direct AMPA agonist properties.<ref name=":2" /> Osavampator provides a 419-fold safety margin against [[convulsion]]s relative to therapeutic doses in rats.<ref name=":2" />
==References==
{{Reflist}}
{{Ionotropic glutamate receptor modulators}}
[[Category:AMPA receptor positive allosteric modulators]]
[[Category:Experimental antidepressants]]
[[Category:Heterocyclic compounds with 2 rings]]
[[Category:Sultams]]
[[Category:Thiazines]]