( 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 appears to be a 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. As of 2016 it was in a Phase II clinical trial for major depressive disorder.
Stylized depiction of an activated NMDAR. Glutamate is in the glutamate-binding site and glycine is in the glycine-binding site.
4-Chlorokynurenine inhibits NMDARs at the glycine binding site.
4-Chlorokynurenine penetrates the
blood–brain barrier via the large neutral amino acid transporter 1. 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
metabolite, 4-chloro-3-hydroxy-anthranilic acid, inhibits the enzyme 3-hydroxyanthranilate oxidase, which provides a rationale for further testing in neurodegenerative diseases.
4-Chlorokynurenine is prodrug of
7-chlorokynurenic acid (7-Cl-KYNA), which in turn is a halogenated derivative of L- kynurenine.
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.  
VistaGen acquired AV-101 when it acquired Artemis in 2003.
VistaGen filed an
Investigational New Drug application with the FDA for use of AV-101 in neuropathic pain in 2013.
In 2013, other
NMDA receptor antagonists in clinical trials for depression included lanicemine, esketamine, and rapastinel, with lanicemine being the most advanced.
AV-101 showed efficacy in
animal model of Huntington's disease and showed rapid-acting antidepressant effects similar to  ketamine in the forced-swim test and two other behavioral models of depression in rodents.
By 2013 AV-101 had successfully gone through two Phase I clinical trials.
As of 2016 a Phase II clinical trial was underway in
major depressive disorder.
By 2019 a phase II clinical trial had shown negative results for major depressive disorder.
It has been found to be effective for neuropathic pain in animal studies.
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