4-Chlorokynurenine Explained

L-4-Chlorokynurenine (4-Cl-KYN; developmental code name AV-101) is an orally active small molecule prodrug of 7-chlorokynurenic acid, a NMDA receptor antagonist. It was investigated as a potential rapid-acting antidepressant.

AV-101 was discovered at Marion Merrell Dow and its biological activity was explored at University of Maryland. It underwent initial development at Artemis Neuroscience which was acquired by VistaGen in 2003. A phase II clinical trial failed to show any effect over placebo in alleviating treatment-resistant depression.[1]

Pharmacology

4-Chlorokynurenine penetrates the blood–brain barrier via the large neutral amino acid transporter 1.[2] In the central nervous system it is converted to 7-chlorokynurenic acid by kynurenine aminotransferase in astrocytes.

Most of its therapeutic potential is believed to occur via 7-chlorokynurenic acid which inhibits the glycine co-agonist site of NMDA receptors.

Another metabolite, 4-chloro-3-hydroxy-anthranilic acid, inhibits the enzyme 3-hydroxyanthranilate oxidase, which provides a rationale for further testing in neurodegenerative diseases.[3]

Chemistry

4-Chlorokynurenine is prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), which in turn is a halogenated derivative of L-kynurenine.[3]

History

Artemis Neuroscience was formed to develop work done by University of Maryland professor Robert Schwartz in collaboration with scientists at Marion Merrell Dow (which became part of Sanofi by way of Aventis); this work included AV-101.[4] [5] [6]

VistaGen acquired AV-101 when it acquired Artemis in 2003.[7]

VistaGen filed an Investigational New Drug application with the FDA for use of AV-101 in neuropathic pain in 2013.[3]

In 2013, other NMDA receptor antagonists in clinical trials for depression included lanicemine, esketamine, and rapastinel, with lanicemine being the most advanced.[8]

Research

By 2013, AV-101 had successfully gone through two Phase I clinical trials. In 2016, a Phase II clinical trial was initiated to assess AV-101 in treatment-resistant major depression. The trial found no difference in treatment effects between AV-101 and placebo.[9]

Preclinical studies in animal models suggested efficacy in treating neuropathic pain.[10] AV-101 showed efficacy in an animal model of Huntington's disease and rapid-acting antidepressant effects similar to ketamine in behavioral models of depression in rodents.[11]

See also

External links

Notes and References

  1. Park LT, Kadriu B, Gould TD, Zanos P, Greenstein D, Evans JW, Yuan P, Farmer CA, Oppenheimer M, George JM, Adeojo LW, Snodgrass HR, Smith MA, Henter ID, Machado-Vieira R, Mannes AJ, Zarate CA . 6 . A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression . The International Journal of Neuropsychopharmacology . 23 . 7 . 417–425 . July 2020 . 32236521 . 7387765 . 10.1093/ijnp/pyaa025 .
  2. Book: Smith QR, Lockman PR . 11. Prodrug Approaches for Central Nervous System Delivery . Mannhold R, Kubinyi H, Folkers G . Prodrugs and Targeted Delivery: Towards Better ADME Properties Volume 47 of Methods and Principles in Medicinal Chemistry. 2011. John Wiley & Sons. 9783527633180 . 259 . https://books.google.com/books?id=jYI5jtMA2qgC&pg=PA259.
  3. Vécsei L, Szalárdy L, Fülöp F, Toldi J . Kynurenines in the CNS: recent advances and new questions . Nature Reviews. Drug Discovery . 12 . 1 . 64–82 . January 2013 . 23237916 . 10.1038/nrd3793 . 31914015 .
  4. Web site: School of Medicine Professor Wins University System of Maryland (USM) Board of Regents Award. University of Maryland. April 6, 2007. January 12, 2017. https://web.archive.org/web/20170113143042/http://somvweb.som.umaryland.edu/absolutenm/templates/?a=143. January 13, 2017. dead.
  5. News: Press Release: VistaGen Therapeutics Acquires Artemis Neuroscience, Inc. - Enters Late-Stage Preclinical Development Program for Lead Epilepsy Drug Candidate -. PR Newswire. November 19, 2003.
  6. Web site: VistaGen Therapeutics, Inc. 8-K Exhibit 10-26. SEC Edgar. May 16, 2011. See 8-K Index page at SEC Edgar.
  7. News: VistaGen acquires Artemis Neuroscience. San Francisco Business Times. November 19, 2003.
  8. Flight MH . Trial watch: phase II boost for glutamate-targeted antidepressants . Nature Reviews. Drug Discovery . 12 . 12 . 897 . December 2013 . 24287771 . 10.1038/nrd4178 . 33113283 . free .
  9. Hashimoto K . Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective . Psychiatry and Clinical Neurosciences . 73 . 10 . 613–627 . October 2019 . 31215725 . 6851782 . 10.1111/pcn.12902 .
  10. Yaksh TL, Schwarcz R, Snodgrass HR . Characterization of the Effects of L-4-Chlorokynurenine on Nociception in Rodents . English . The Journal of Pain . 18 . 10 . 1184–1196 . October 2017 . 28428091 . 10.1016/j.jpain.2017.03.014 . free .
  11. Gerhard DM, Wohleb ES, Duman RS . Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity . Drug Discovery Today . 21 . 3 . 454–464 . March 2016 . 26854424 . 4803609 . 10.1016/j.drudis.2016.01.016 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "4-Chlorokynurenine".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.