7-Chlorokynurenic acid

Last updated
7-Chlorokynurenic acid
7-Chlorokynurenic acid.svg
Names
Preferred IUPAC name
7-Chloro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid
Other names
7-Chlorokynurenate; 7-CTKA
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.038.088 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 241-913-6
PubChem CID
UNII
  • InChI=1S/C10H6ClNO3/c11-5-1-2-6-7(3-5)12-8(10(14)15)4-9(6)13/h1-4H,(H,12,13)(H,14,15)
    Key: UAWVRVFHMOSAPU-UHFFFAOYSA-N
  • 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).

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]

See also

References

  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.
  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.
  4. 1 2 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.
  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.
  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.
  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.
  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.


This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.