7-Chlorokynurenic acid
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Preferred IUPAC name 7-Chloro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid | |
Other names 7-Chlorokynurenate; 7-CTKA | |
Identifiers | |
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3D model (JSmol) |
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ChemSpider |
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ECHA InfoCard | 100.038.088 |
PubChem CID |
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Properties | |
Chemical formula | 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). Infobox references |
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.
- v
- t
- e
- Agonists: Main site agonists: 5-Fluorowillardiine
- Acromelic acid (acromelate)
- AMPA
- BOAA
- Domoic acid
- Glutamate
- Ibotenic acid
- Proline
- Quisqualic acid
- Willardiine; Positive allosteric modulators: Aniracetam
- Cyclothiazide
- CX-516
- CX-546
- CX-614
- Farampator (CX-691, ORG-24448)
- CX-717
- CX-1739
- CX-1942
- Diazoxide
- Hydrochlorothiazide (HCTZ)
- IDRA-21
- LY-392098
- LY-395153
- LY-404187
- LY-451646
- LY-503430
- Mibampator (LY-451395)
- Nooglutyl
- ORG-26576
- Oxiracetam
- PEPA
- Pesampator (BIIB-104, PF-04958242)
- Piracetam
- Pramiracetam
- S-18986
- Tulrampator (S-47445, CX-1632)
- Antagonists: ACEA-1011
- ATPO
- Becampanel
- Caroverine
- CNQX
- Dasolampanel
- DNQX
- Fanapanel (MPQX)
- GAMS
- Kaitocephalin
- Kynurenic acid
- Kynurenine
- Licostinel (ACEA-1021)
- NBQX
- PNQX
- Selurampanel
- Tezampanel
- Theanine
- Topiramate
- YM90K
- Zonampanel; Negative allosteric modulators: Barbiturates (e.g., pentobarbital, sodium thiopental)
- Cyclopropane
- Enflurane
- Ethanol (alcohol)
- Evans blue
- GYKI-52466
- GYKI-53655
- Halothane
- Irampanel
- Isoflurane
- Perampanel
- Pregnenolone sulfate
- Sevoflurane
- Talampanel; Unknown/unsorted antagonists: Minocycline
- Agonists: Main site agonists: 5-Bromowillardiine
- 5-Iodowillardiine
- Acromelic acid (acromelate)
- AMPA
- ATPA
- Domoic acid
- Glutamate
- Ibotenic acid
- Kainic acid
- LY-339434
- Proline
- Quisqualic acid
- SYM-2081; Positive allosteric modulators: Cyclothiazide
- Diazoxide
- Enflurane
- Halothane
- Isoflurane
- Antagonists: ACEA-1011
- CNQX
- Dasolampanel
- DNQX
- GAMS
- Kaitocephalin
- Kynurenic acid
- Licostinel (ACEA-1021)
- LY-382884
- NBQX
- NS102
- Selurampanel
- Tezampanel
- Theanine
- Topiramate
- UBP-302; Negative allosteric modulators: Barbiturates (e.g., pentobarbital, sodium thiopental)
- Enflurane
- Ethanol (alcohol)
- Evans blue
- NS-3763
- Pregnenolone sulfate
- Agonists: Main site agonists: AMAA
- Aspartate
- Glutamate
- Homocysteic acid (L-HCA)
- Homoquinolinic acid
- Ibotenic acid
- NMDA
- Proline
- Quinolinic acid
- Tetrazolylglycine
- Theanine; Glycine site agonists: β-Fluoro-D-alanine
- ACBD
- ACC (ACPC)
- ACPD
- AK-51
- Apimostinel (NRX-1074)
- B6B21
- CCG
- D-Alanine
- D-Cycloserine
- D-Serine
- DHPG
- Dimethylglycine
- Glycine
- HA-966
- L-687414
- L-Alanine
- L-Serine
- Milacemide
- Neboglamine (nebostinel)
- Rapastinel (GLYX-13)
- Sarcosine; Polyamine site agonists: Neomycin
- Spermidine
- Spermine; Other positive allosteric modulators: 24S-Hydroxycholesterol
- DHEATooltip Dehydroepiandrosterone (prasterone)
- DHEA sulfate (prasterone sulfate)
- Epipregnanolone sulfate
- Plazinemdor
- Pregnenolone sulfate
- SAGE-201
- SAGE-301
- SAGE-718
- Antagonists: Competitive antagonists: AP5 (APV)
- AP7
- CGP-37849
- CGP-39551
- CGP-39653
- CGP-40116
- CGS-19755
- CPP
- Kaitocephalin
- LY-233053
- LY-235959
- LY-274614
- MDL-100453
- Midafotel (d-CPPene)
- NPC-12626
- NPC-17742
- PBPD
- PEAQX
- Perzinfotel
- PPDA
- SDZ-220581
- Selfotel; Glycine site antagonists: 4-Cl-KYN (AV-101)
- 5,7-DCKA
- 7-CKA
- ACC
- ACEA-1011
- ACEA-1328
- Apimostinel (NRX-1074)
- AV-101
- Carisoprodol
- CGP-39653
- CNQX
- D-Cycloserine
- DNQX
- Felbamate
- Gavestinel
- GV-196771
- Harkoseride
- Kynurenic acid
- Kynurenine
- L-689560
- L-701324
- Licostinel (ACEA-1021)
- LU-73068
- MDL-105519
- Meprobamate
- MRZ 2/576
- PNQX
- Rapastinel (GLYX-13)
- ZD-9379; Polyamine site antagonists: Arcaine
- Co 101676
- Diaminopropane
- Diethylenetriamine
- Huperzine A
- Putrescine; Uncompetitive pore blockers (mostly dizocilpine site): 2-MDP
- 3-HO-PCP
- 3-MeO-PCE
- 3-MeO-PCMo
- 3-MeO-PCP
- 4-MeO-PCP
- 8A-PDHQ
- 18-MC
- α-Endopsychosin
- Alaproclate
- Alazocine (SKF-10047)
- Amantadine
- Aptiganel
- Argiotoxin-636
- Arketamine
- ARL-12495
- ARL-15896-AR
- ARL-16247
- Budipine
- Coronaridine
- Delucemine (NPS-1506)
- Dexoxadrol
- Dextrallorphan
- Dextromethadone
- Dextromethorphan
- Dextrorphan
- Dieticyclidine
- Diphenidine
- Dizocilpine
- Ephenidine
- Esketamine
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- Eticyclidine
- Fluorolintane
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- Ibogaine
- Ibogamine
- Indantadol
- Ketamine
- Ketobemidone
- Lanicemine
- Levomethadone
- Levomethorphan
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- Levorphanol
- Loperamide
- Memantine
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- Methorphan
- Methoxetamine
- Methoxphenidine
- Milnacipran
- Morphanol
- NEFA
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- Nitromemantine
- Noribogaine
- Norketamine
- Orphenadrine
- PCPr
- PD-137889
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- Phencyclamine
- Phencyclidine
- Propoxyphene
- Remacemide
- Rhynchophylline
- Rimantadine
- Rolicyclidine
- Sabeluzole
- Tabernanthine
- Tenocyclidine
- Tiletamine
- Tramadol; Ifenprodil (NR2B) site antagonists:
- Besonprodil
- Buphenine (nylidrin)
- CO-101244 (PD-174494)
- Eliprodil
- Haloperidol
- Isoxsuprine
- Radiprodil (RGH-896)
- Rislenemdaz (CERC-301, MK-0657)
- Ro 8-4304
- Ro 25-6981
- Safaprodil
- Traxoprodil (CP-101606); NR2A-selective antagonists: MPX-004
- MPX-007
- TCN-201
- TCN-213; Cations: Hydrogen
- Magnesium
- Zinc; Alcohols/volatile anesthetics/related: Benzene
- Butane
- Chloroform
- Cyclopropane
- Desflurane
- Diethyl ether
- Enflurane
- Ethanol (alcohol)
- Halothane
- Hexanol
- Isoflurane
- Methoxyflurane
- Nitrous oxide
- Octanol
- Sevoflurane
- Toluene
- Trichloroethane
- Trichloroethanol
- Trichloroethylene
- Urethane
- Xenon
- Xylene; Unknown/unsorted antagonists: ARR-15896
- Bumetanide
- Caroverine
- Conantokin
- D-αAA
- Dexanabinol
- Flufenamic acid
- Flupirtine
- FPL-12495
- FR-115427
- Furosemide
- Hodgkinsine
- Ipenoxazone (MLV-6976)
- MDL-27266
- Metaphit
- Minocycline
- MPEP
- Niflumic acid
- Pentamidine
- Pentamidine isethionate
- Piretanide
- Psychotridine
- Transcrocetin (saffron)
- Unsorted: Allosteric modulators: AGN-241751
- See also: Receptor/signaling modulators
- Metabotropic glutamate receptor modulators
- Glutamate metabolism/transport modulators