Osavampator

Osavampator is a selective positive allosteric modulator (PAM) of the AMPA receptor.{{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 }}{{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 }} Osavampator 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.{{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 }}

The terminal half-life of osavampator is 33.1–47.8 hours.{{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 }}

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 antagonists such as ketamine.{{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 }} Blockage of the AMPA receptor nullifies the antidepressant actions of ketamine in rodents.{{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 }} By potentiating the effect of endogenous glutamate at the AMPA receptor, osavampator more directly influences AMPA receptor-mediated transcription.

The potential use of osavampator as a non-psychotomimetic antidepressant is cited as reason for its investigation. Initial research found that osavampator, unlike ketamine, did not induce 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. No severe adverse effects were noted in the trial.

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.{{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 }}{{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 }}{{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 }} Osavampator possesses minimal direct AMPA agonist properties. Osavampator provides a 419-fold safety margin against convulsions relative to therapeutic doses in rats.

{{Reflist}}

{{Ionotropic glutamate receptor modulators}}

Category:AMPA receptor positive allosteric modulators

Category:Experimental antidepressants

Category:Heterocyclic compounds with 2 rings

Category:Sultams

Category:Thiazines