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7-Chlorokynurenic acid

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7-Chlorokynurenic acid (7-CKA) is a tool compound that acts as a potent and selective competitive antagonist of the glycine site of the NMDA receptor.[1] It produces ketamine-like rapid antidepressant effects in animal models of depression.[2][3] However, 7-CKA is unable to cross the blood-brain-barrier, and for this reason, is unsuitable for clinical use.[4] As a result, a centrally-penetrant prodrug of 7-CKA, 4-chlorokynurenine (AV-101), has been developed for use in humans, and is being studied in clinical trials as a potential treatment for major depressive disorder,[4][5][6] and anti-nociception.[7] In addition to antagonizing the NMDA receptor, 7-CKA also acts as a potent inhibitor of the reuptake of glutamate into synaptic vesicles (or as a vesicular glutamate reuptake inhibitor), an action that it mediates via competitive blockade of vesicular glutamate transporters (Ki = 0.59 mM).[8]

7-Chlorokynurenic acid
Names
Preferred IUPAC name
7-Chloro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid
Other names
7-Chlorokynurenate; 7-CTKA
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.038.088 Edit this at Wikidata
UNII
  • C1=CC2=C(C=C1Cl)NC(=CC2=O)C(=O)O
Properties
C10H6ClNO3
Molar mass 223.61 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

See also

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References

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  1. ^ Kemp JA, Foster AC, Leeson PD, Priestley T, Tridgett R, Iversen LL, Woodruff GN (1988). "7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex". Proc. Natl. Acad. Sci. U.S.A. 85 (17): 6547–50. Bibcode:1988PNAS...85.6547K. doi:10.1073/pnas.85.17.6547. PMC 282010. PMID 2842779.6547-50&rft.date=1988&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC282010#id-name=PMC&rft_id=info:pmid/2842779&rft_id=info:doi/10.1073/pnas.85.17.6547&rft_id=info:bibcode/1988PNAS...85.6547K&rft.aulast=Kemp&rft.aufirst=JA&rft.au=Foster, AC&rft.au=Leeson, PD&rft.au=Priestley, T&rft.au=Tridgett, R&rft.au=Iversen, LL&rft.au=Woodruff, GN&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC282010&rfr_id=info:sid/en.wikipedia.org:7-Chlorokynurenic acid" class="Z3988">
  2. ^ Zhang, Ke; Xu, Ting; Yuan, Zhongmin; Wei, Zhisheng; Yamaki, Vitor Nagai; Huang, Mingfa; Huganir, Richard L.; Cai, Xiang (2016-12-13). "Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine". Sci. Signal. 9 (458): ra123. doi:10.1126/scisignal.aai7884. ISSN 1945-0877. PMC 5564288. PMID 27965425.
  3. ^ Zanos, Panos; Piantadosi, Sean C.; Wu, Hui-Qiu; Pribut, Heather J.; Dell, Matthew J.; Can, Adem; Snodgrass, H. Ralph; Zarate, Carlos A.; Schwarcz, Robert (October 2015). "The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/GlycineB-Site Inhibition". The Journal of Pharmacology and Experimental Therapeutics. 355 (1): 76–85. doi:10.1124/jpet.115.225664. ISSN 1521-0103. PMC 4576668. PMID 26265321.76-85&rft.date=2015-10&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576668#id-name=PMC&rft.issn=1521-0103&rft_id=info:pmid/26265321&rft_id=info:doi/10.1124/jpet.115.225664&rft.aulast=Zanos&rft.aufirst=Panos&rft.au=Piantadosi, Sean C.&rft.au=Wu, Hui-Qiu&rft.au=Pribut, Heather J.&rft.au=Dell, Matthew J.&rft.au=Can, Adem&rft.au=Snodgrass, H. Ralph&rft.au=Zarate, Carlos A.&rft.au=Schwarcz, Robert&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576668&rfr_id=info:sid/en.wikipedia.org:7-Chlorokynurenic acid" class="Z3988">
  4. ^ a b Hokari M, Wu HQ, Schwarcz R, Smith QR (1996). "Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid". NeuroReport. 8 (1): 15–8. doi:10.1097/00001756-199612200-00004. PMID 9051744. S2CID 32729671.15-8&rft.date=1996&rft_id=https://api.semanticscholar.org/CorpusID:32729671#id-name=S2CID&rft_id=info:pmid/9051744&rft_id=info:doi/10.1097/00001756-199612200-00004&rft.aulast=Hokari&rft.aufirst=M&rft.au=Wu, HQ&rft.au=Schwarcz, R&rft.au=Smith, QR&rft_id=https://zenodo.org/record/1234762&rfr_id=info:sid/en.wikipedia.org:7-Chlorokynurenic acid" class="Z3988">
  5. ^ Gerhard, Danielle M.; Wohleb, Eric S.; Duman, Ronald S. (March 2016). "Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity". Drug Discovery Today. 21 (3): 454–464. doi:10.1016/j.drudis.2016.01.016. ISSN 1878-5832. PMC 4803609. PMID 26854424.454-464&rft.date=2016-03&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803609#id-name=PMC&rft.issn=1878-5832&rft_id=info:pmid/26854424&rft_id=info:doi/10.1016/j.drudis.2016.01.016&rft.aulast=Gerhard&rft.aufirst=Danielle M.&rft.au=Wohleb, Eric S.&rft.au=Duman, Ronald S.&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803609&rfr_id=info:sid/en.wikipedia.org:7-Chlorokynurenic acid" class="Z3988">
  6. ^ Vécsei, László; Szalárdy, Levente; Fülöp, Ferenc; Toldi, József (2012). "Kynurenines in the CNS: recent advances and new questions". Nature Reviews Drug Discovery. 12 (1): 64–82. doi:10.1038/nrd3793. ISSN 1474-1776. PMID 23237916. S2CID 31914015.64-82&rft.date=2012&rft.issn=1474-1776&rft_id=https://api.semanticscholar.org/CorpusID:31914015#id-name=S2CID&rft_id=info:pmid/23237916&rft_id=info:doi/10.1038/nrd3793&rft.aulast=Vécsei&rft.aufirst=László&rft.au=Szalárdy, Levente&rft.au=Fülöp, Ferenc&rft.au=Toldi, József&rfr_id=info:sid/en.wikipedia.org:7-Chlorokynurenic acid" class="Z3988">
  7. ^ Wallace, Mark; White, Alexander; Grako, Kathy A.; Lane, Randal; Cato, Allen (Jo); Snodgrass, H. Ralph (2017-06-14). "Randomized, double-blind, placebo-controlled, dose-escalation study: Investigation of the safety, pharmacokinetics, and antihyperalgesic activity of l-4-chlorokynurenine in healthy volunteers". Scandinavian Journal of Pain. 17 (1): 243–251. doi:10.1016/j.sjpain.2017.05.004. ISSN 1877-8860. PMID 29229209. S2CID 46873455.243-251&rft.date=2017-06-14&rft.issn=1877-8860&rft_id=https://api.semanticscholar.org/CorpusID:46873455#id-name=S2CID&rft_id=info:pmid/29229209&rft_id=info:doi/10.1016/j.sjpain.2017.05.004&rft.aulast=Wallace&rft.aufirst=Mark&rft.au=White, Alexander&rft.au=Grako, Kathy A.&rft.au=Lane, Randal&rft.au=Cato, Allen (Jo)&rft.au=Snodgrass, H. Ralph&rft_id=http://www.scandinavianjournalpain.com/article/S1877-8860(17)30128-3/abstract&rfr_id=info:sid/en.wikipedia.org:7-Chlorokynurenic acid" class="Z3988">
  8. ^ Bartlett RD, Esslinger CS, Thompson CM, Bridges RJ (1998). "Substituted quinolines as inhibitors of L-glutamate transport into synaptic vesicles". Neuropharmacology. 37 (7): 839–46. doi:10.1016/s0028-3908(98)00080-x. PMID 9776380. S2CID 39853026.839-46&rft.date=1998&rft_id=https://api.semanticscholar.org/CorpusID:39853026#id-name=S2CID&rft_id=info:pmid/9776380&rft_id=info:doi/10.1016/s0028-3908(98)50080-x&rft.aulast=Bartlett&rft.aufirst=RD&rft.au=Esslinger, CS&rft.au=Thompson, CM&rft.au=Bridges, RJ&rfr_id=info:sid/en.wikipedia.org:7-Chlorokynurenic acid" class="Z3988">


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