4-Chlorokynurenine

4-Chlorokynurenine
Clinical data
Pregnancy
category
  • US: N (Not classified yet)
Routes of
administration		 Oral
ATC code None
Legal status
Legal status
Pharmacokinetic data
Bioavailability 39–84% (rodents); ≥ 31% (humans)
Biological half-life 2–3 hours
Identifiers
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

References

  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

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