Clinical data
  • US: N (Not classified yet)
Routes of
ATC code None
Legal status
Legal status
Pharmacokinetic data
Bioavailability 39–84% (rodents); ≥ 31% (humans)
Biological half-life 2–3 hours
Synonyms 3-(4-Chloroanthraniloyl)-DL-alanine
CAS Number 75802-84-5
PubChem (CID) 9859632
ChemSpider 151423
Chemical and physical data
Formula C10H11ClN2O3
Molar mass 242.65894 g/mol
3D model (Jmol) Interactive image

L-4-Chlorokynurenine (4-Cl-KYN; developmental code name AV-101) is an orally active small molecule prodrug candidate that in vivo produces a glycine binding site NMDA receptor antagonist. AV-101 is in clinical development by VistaGen Therapeutics. Inc. as a potential new generation, fast-acting antidepressant,[1][2] and for other central nervous system (CNS) indications. The initial Phase 2 clinical study of AV-101 is expected to begin in 2015 and will be focused on treatment-resistant depression (TRD) and major depressive disorder (MDD).[3]

Therapeutic indications and mechanism of action

AV-101, or its active metabolite 7-chlorokynurenic acid (7-Cl-KYNA), shows neuroprotective effects in animal models of excitotoxic neurotoxicity[4][5][6] anticonvulsant effects in animal models of epilepsy,[7][8] and depression,[1][9][10] and has been found to activate dopaminergic neurons.[11]

Currently-approved antidepressants, including commonly-prescribed selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), have limited effectiveness.[12] Approximately one-third of patients with MDD are not effectively treated by the currently-approved antidepressants, and because of their mechanism of action (MOA), SSRIs and SNRIs must be taken for several weeks before patients experience any significant therapeutic benefit. AV-101’s MOA is fundamentally different from the MOA of SSRIs, SNRIs and all other approved medications for treating depression, placing it together with Ketamine, Rapastinel (GLYX-13) and other new generation of safe, fast-acting, glutamatergic antidepressants under development. This new generation of antidepressants target the N-methyl-D-aspartate receptor (NMDA receptor or NMDAR), or the glycine co-agonist site of the NMDAR, and have the potential to treat the millions of depression sufferers who are poorly served by SSRIs, SNRIs and other existing medications.[13][14]

In vivo, AV-101 is converted into active 7-Cl-KYNA, one of the most potent and selective NMDAR glycine binding site antagonists,[4][6][15] and therefore, unlike classic NMDA receptor antagonists, such as ketamine, phencyclidine (PCP), lanicemine, and dizocilpine (MK-801), instead of blocking the ion channel, AV-101 down-regulates the NMDAR activity. AV-101 is an orally-available prodrug,[16] which is in contrast to ketamine, and other new generation NMDA receptor modulators, such as the peptide rapastinel (GLYX-13), that are given via intravenous injection. AV-101 is efficiently and rapidly transported across the blood–brain barrier (BBB) by neutral amino acid transporter, and is converted in the brain into 7-Cl-KYNA.[4][6][17] Although 7-Cl-KYNA, is well known as one of the most potent and selective antagonists of the glycine regulatory site of the NMDAR, and its neuroprotective and antidepressant activities have been well documented,[5][9][10][15] 7-Cl-KYNA does not cross the BBB and therefore is not suitable as a drug for CNS indications.[17]

The Central Nervous System (CNS) conversion of AV-101 into active 7-Cl-KYNA, takes place primarily in astrocytes, and is catalyzed by kynurenine aminotransferases, KAT I and KAT II.[18][19] Once produced, 7-Cl-KYNA is released into the synapse where it is able to help regulate post-synaptic neurons as well as GABAergic interneurons.[20] The KAT enzymes are involved in the kynurenine pathway associated with the metabolism of the amino acid tryptophan and the production of kynurenic acid (KYNA).[18][21] KYNA is a natural neuroactive compound with known anti-excitotoxic and anticonvulsant properties, which help regulate dopaminergic pathways.[21][22][23][24] The biology of the kynurenines, and the regulation of the conversion of AV-101 into active 7-Cl-KYNA have significant therapeutic importance.[19][21] The expression of the KAT enzymes is significantly upregulated in areas of inflammation, neuronal damage, and other pathological processes, which results in a local increase in the production of 7-Cl-KYNA,[25] which may result in a focal increase of the active drug in the regions of pathology and greatest therapeutic need.

The metabolism of AV-101 has an additional potential therapeutic benefit, due to its potential to down regulate the production of quinolinic acid (QA). In addition to the production of 7-Cl-KYNA, AV-101 is also metabolized to 4-Cl-3-hydroxyanthranilic acid,[26] a potent inhibitor of 3-hydroxyanthranilic acid oxygenase (3HAO) (IC50: ~6 nM), the enzyme responsible for the production of QA synthesis.[27] QA is a potent NMDA receptor agonist, convulsant, and endogenous excitotoxic brain constituent.[28] Abnormal increase in the QA/KYNA ratio in the brain has been associated with seizures and excitotoxic neurodegeneration,[4] as well as neurological pathologies such as Huntington’s disease,[29] seizures,[30] and depression,[31][32] and schizophrenia.[33]

Clinical status

AV-101 has completed two double-blind, placebo-controlled Phase 1 clinical safety studies funded by the U.S. National Institutes of Health (NIH). Both of these NIH-funded Phase 1 safety studies demonstrated that AV-101 is safe and well-tolerated, even at the highest dose studied, with the frequency and degree of adverse events no different than seen in the placebo control groups.[3][34]

Under the February 2015 Cooperative Research and Development Agreement (CRADA) between VistaGen and the NIH, an NIH-sponsored, double-blind, placebo-controlled Phase 2 clinical study of AV-101 in patients with treatment-resistant MDD will be initiated at the U.S. National Institute of Mental Health (NIMH) in 2015.[35]

See also


  1. 1 2 Zanos, P., et al. (2015) The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/GlycineB-Site Inhibition. J Pharmacol Exp Ther 355:76-85. DOI: 10.1124/jpet.115.225664
  2. Flight MH. (2013) Trial watch: phase II boost for glutamate-targeted antidepressants. Nat Rev Drug Discov 12: 897. DOI: 10.1038/nrd4178, PMID 24287771
  3. 1 2 http://finance.yahoo.com/news/vistagen-therapeutics-successfully-completes-final-133000505.html
  4. 1 2 3 4 Wu HQ, et al. (1997) Enzyme-catalyzed production of the neuroprotective NMDA receptor antagonist 7-chlorokynurenic acid in the rat brain in vivo. Eur J Pharmacol 319: 13-20. PMID 9030892.
  5. 1 2 Wu HQ, et al. (2000) Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus. Eur J Pharmacol 390: 267-274. PMID 10708733.
  6. 1 2 3 Guidetti P, et al. (2000) In situ produced 7-chlorokynurenate provides protection against quinolinate- and malonate-induced neurotoxicity in the rat striatum. Exp Neurol 163: 123-130. DOI: 10.1006/exnr.1999.7284, PMID 10785450.
  7. Wu HQ, et al. (2002) L-4-chlorokynurenine attenuates kainate-induced seizures and lesions in the rat. Exp Neurol 177: 222-232. PMID 12429224.
  8. Wu HQ, et al. (2005) Kynurenate and 7-chlorokynurenate formation in chronically epileptic rats. Epilepsia 46: 1010-1016. DOI: 10.1111/j.1528-1167.2005.67404.x, PMID 16026552.
  9. 1 2 Zhu WL, et al. (2013) Glycine site N-methyl-D-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats. J Psychiatry Neurosci 38: 306-316. DOI: 10.1503/jpn.120228, PMID 23611177.
  10. 1 2 Liu BB, et al. (2015) 7-Chlorokynurenic acid (7-CTKA) produces rapid antidepressant-like effects: through regulating hippocampal microRNA expressions involved in TrkB-ERK/Akt signaling pathways in mice exposed to chronic unpredictable mild stress. Psychopharmacology (Berl) 232: 541-550. DOI: 10.1007/s00213-014-3690-3, PMID 25034119.
  11. Linderholm KR, et al. (2007) Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis. Neuropharmacology 53: 918-924. DOI: 10.1016/j.neuropharm.2007.09.003, PMID 17959203.
  12. Rush AJ, et al. (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163: 1905-1917. DOI: 10.1176/appi.ajp.163.11.1905, PMID 17074942.
  13. Dolgin E. (2013) Rapid antidepressant effects of ketamine ignite drug discovery. Nat Med 19: 8. DOI: 10.1038/nm0113-8, PMID 23295995.
  14. Murrough JW. (2015) Glutamate NMDA receptor modulators for the treatment of depression: trials and tribulations. Psychopharmacology (Berl) 232: 1497-1499. DOI: 10.1007/s00213-015-3888-z, PMID 25752888.
  15. 1 2 Kemp JA, et al. (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 USA 85: 6547-6550. PMID 2842779.
  16. http://www.reuters.com/article/2010/12/20/idUS161036+20-Dec-2010+BW20101220
  17. 1 2 Hokari M, et al. (1996) Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid. Neuroreport 8: 15-18. PMID 9051744.
  18. 1 2 Kiss C, et al. (2003) Kynurenate production by cultured human astrocytes. J Neural Transm 110: 1-14. DOI: 10.1007/s00702-002-0770-z, PMID 12541009.
  19. 1 2 Schwarcz, R., et al. (2012) "Kynurenines in the mammalian brain: when physiology meets pathology." Nat Rev Neurosci 13:465-477. PMID 22678511.
  20. Iadarola ND, et al. (2015) Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. Ther Adv Chronic Dis 6: 97-114. DOI: 10.1177/2040622315579059, PMID 25954495.
  21. 1 2 3 Vecsei L, et al. (2013). Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov 12: 64-82. DOI: 10.1038/nrd3793, PMID 23237916.
  22. Winn P, et al. (1991) A comparison of excitotoxic lesions of the basal forebrain by kainate, quinolinate, ibotenate, N-methyl-D-aspartate or quisqualate, and the effects on toxicity of 2-amino-5-phosphonovaleric acid and kynurenic acid in the rat. Br J Pharmacol 102: 904-908. PMID 1677299.
  23. Carpenedo R, et al. (2001) Presynaptic kynurenate-sensitive receptors inhibit glutamate release. Eur J Neurosci 13: 2141-2147. PMID 11422455.
  24. Wu HQ, et al. (2010) The astrocyte-derived alpha7 nicotinic receptor antagonist kynurenic acid controls extracellular glutamate levels in the prefrontal cortex. J Mol Neurosci 40: 204-210. DOI: 10.1007/s12031-009-9235-2, PMID 19690987.
  25. Lee, S. C. and R. Schwarcz (2001) "Excitotoxic injury stimulates pro-drug-induced 7-chlorokynurenate formation in the rat striatum in vivo." Neurosci Lett 304:185-188. PMID 11343833.
  26. Guidetti, P., et al. (2000) "In situ produced 7-chlorokynurenate provides protection against quinolinate- and malonate-induced neurotoxicity in the rat striatum." Exp Neurol 163:123-130. PMID 10785450.
  27. Walsh, J. L., et al. (1991) "4-halo-3-hydroxyanthranilic acids: potent competitive inhibitors of 3-hydroxy-anthranilic acid oxygenase in vitro." Biochem Pharmacol 42:985-990. PMID 1831362.
  28. Guillemin, Giles (April 2012). "Quinolinic acid, the inescapable neurotoxin". FEBS Journal 279 (8): 1356–1365. doi:10.1111/j.1742-4658.2012.08485.x. PMID 22248144.
  29. Schwarcz, R., et al. (2010) "Of mice, rats and men: Revisiting the quinolinic acid hypothesis of Huntington's disease." Prog Neurobiol 90:230-245. PMID 19394403.
  30. Tavares, R. G., et al. (2008) "Quinolinic acid-induced seizures stimulate glutamate uptake into synaptic vesicles from rat brain: effects prevented by guanine-based purines." Neurochem Res 33:97-102. PMID 17682941.
  31. Bay-Richter, C., et al. (2015) "A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality." Brain Behav Immun 43:110-117. PMID 25124710.
  32. Savitz, J., et al. (2015) "Reduction of kynurenic acid to quinolinic acid ratio in both the depressed and remitted phases of major depressive disorder." Brain Behav Immun. Doi: 10.1016/j.bbi.2015.02.007. PMID 25686798.
  33. Balu DT and Coyle JT. (2015). The NMDA receptor 'glycine modulatory site' in schizophrenia: d-serine, glycine, and beyond. Curr Opin Pharmacol 20C: 109-115. DOI: 10.1016/j.coph.2014.12.004, PMID 25540902.
  34. https://clinicaltrials.gov/ct2/show/NCT01483846?term=vistagen&rank=1.
  35. http://www.reuters.com/article/2015/02/17/idUSnMKWzFcqra+1d0+MKW20150217

External links

This article is issued from Wikipedia - version of the 9/25/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.