From Wikipedia, the free encyclopedia
Chemical compound
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
^ 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 .
^ 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 .
^ 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 .
^
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 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
AMPAR Tooltip α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
KAR Tooltip Kainate receptor
NMDAR Tooltip N-Methyl-D-aspartate receptor
Transporter
EAATs Tooltip Excitatory amino acid transporters
vGluTs Tooltip Vesicular glutamate transporters
Enzyme
GAH Tooltip Glutamine aminohydrolase (glutaminase)
AST Tooltip Aspartate aminotransferase
ALT Tooltip Alanine aminotransferase
GDH Tooltip Glutamate dehydrogenase
GS Tooltip Glutamine synthetase
GAD Tooltip Glutamate decarboxylase