7-Chlorokynurenic acid explained

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,[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

Notes and References

  1. Kemp JA, Foster AC, Leeson PD, Priestley T, Tridgett R, Iversen LL, Woodruff GN . 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 . 1988 . 2842779 . 282010 . 10.1073/pnas.85.17.6547. 1988PNAS...85.6547K . free .
  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.. en. 9. 458. ra123. 10.1126/scisignal.aai7884. 1945-0877. 27965425. 5564288.
  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. 10.1124/jpet.115.225664. 1521-0103. 4576668. 26265321.
  4. Hokari M, Wu HQ, Schwarcz R, Smith QR . Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid . NeuroReport . 8 . 1 . 15–8 . 1996 . 9051744 . 10.1097/00001756-199612200-00004. 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. 10.1016/j.drudis.2016.01.016. 1878-5832. 4803609. 26854424.
  6. Vécsei. László. Szalárdy. Levente. Fülöp. Ferenc. Toldi. József. Kynurenines in the CNS: recent advances and new questions. Nature Reviews Drug Discovery. 12. 1. 2012. 64–82. 1474-1776. 10.1038/nrd3793. 23237916. 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. en. 1. 243–251. 10.1016/j.sjpain.2017.05.004. 29229209. 46873455. 1877-8860.
  8. Bartlett RD, Esslinger CS, Thompson CM, Bridges RJ . Substituted quinolines as inhibitors of L-glutamate transport into synaptic vesicles . Neuropharmacology . 37 . 7 . 839–46 . 1998 . 9776380 . 10.1016/s0028-3908(98)00080-x. 39853026 .

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