Investigational antidepressant compound
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
Stylized depiction of an activated NMDAR. Glutamate is in the glutamate-binding site and glycine is in the glycine-binding site.
[2] 4-Chlorokynurenine inhibits NMDARs at the glycine binding site.
4-Chlorokynurenine penetrates the
blood–brain barrier via the
large neutral amino acid transporter 1 .
[3] In the
central nervous system it is converted to 7-chlorokynurenic acid by
kynurenine aminotransferase in
astrocytes .
[4]
Most of its therapeutic potential is believed to occur via 7-chlorokynurenic acid which inhibits the glycine co-agonist site of
NMDA receptors .
[4]
Another
metabolite , 4-chloro-3-hydroxy-anthranilic acid, inhibits the enzyme
3-hydroxyanthranilate oxidase , which provides a rationale for further testing in neurodegenerative diseases.
[4]
Chemistry
4-Chlorokynurenine is prodrug of
7-chlorokynurenic acid (7-Cl-KYNA), which in turn is a halogenated derivative of L -
kynurenine .
[4]
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.
[5]
[6]
[7]
VistaGen acquired AV-101 when it acquired Artemis in 2003.
[8]
VistaGen filed an
Investigational New Drug application with the FDA for use of AV-101 in
neuropathic pain in 2013.
[4]
In 2013, other
NMDA receptor antagonists in clinical trials for depression included
lanicemine ,
esketamine , and
rapastinel , with lanicemine being the most advanced.
[9]
Research
By 2013, AV-101 had successfully gone through two Phase I clinical trials.
[4] In 2016, a Phase II clinical trial was initiated to assess AV-101 in treatment-resistant
major depression .
[10] The trial found no difference in treatment effects between AV-101 and placebo.
[1]
[11]
Preclinical studies in
animal models suggested efficacy in treating neuropathic pain.
[12] AV-101 showed efficacy in an animal model of
Huntington's disease
[4] and rapid-acting antidepressant effects similar to
ketamine in
behavioral models of depression in rodents.
[10]
See also
References
^
a
b Park LT, Kadriu B, Gould TD, Zanos P, Greenstein D, Evans JW, et al. (July 2020).
"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.
doi :
10.1093/ijnp/pyaa025 .
PMC
7387765 .
PMID
32236521 .
^ Laube B, Hirai H, Sturgess M, Betz H, Kuhse J (March 1997).
"Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit" . Neuron . 18 (3): 493–503.
doi :
10.1016/S0896-6273(00)81249-0 .
PMID
9115742 .
^ Smith QR, Lockman PR (2011).
"11. Prodrug Approaches for Central Nervous System Delivery" . In Mannhold R, Kubinyi H, Folkers G (eds.). Prodrugs and Targeted Delivery: Towards Better ADME Properties Volume 47 of Methods and Principles in Medicinal Chemistry . John Wiley & Sons. p. 259.
ISBN
9783527633180 .
^
a
b
c
d
e
f
g Vécsei L, Szalárdy L, Fülöp F, Toldi J (January 2013). "Kynurenines in the CNS: recent advances and new questions". Nature Reviews. Drug Discovery . 12 (1): 64–82.
doi :
10.1038/nrd3793 .
PMID
23237916 .
S2CID
31914015 .
^
"School of Medicine Professor Wins University System of Maryland (USM) Board of Regents Award" . University of Maryland. April 6, 2007. Archived from
the original on January 13, 2017. Retrieved January 12, 2017 .
^
"Press Release: VistaGen Therapeutics Acquires Artemis Neuroscience, Inc. - Enters Late-Stage Preclinical Development Program for Lead Epilepsy Drug Candidate -" . PR Newswire . November 19, 2003.
^
"VistaGen Therapeutics, Inc. 8-K Exhibit 10-26" . SEC Edgar. May 16, 2011. See
8-K Index page at SEC Edgar.
^
"VistaGen acquires Artemis Neuroscience" . San Francisco Business Times . November 19, 2003.
^ Flight MH (December 2013).
"Trial watch: phase II boost for glutamate-targeted antidepressants" . Nature Reviews. Drug Discovery . 12 (12): 897.
doi :
10.1038/nrd4178 .
PMID
24287771 .
S2CID
33113283 .
^
a
b Gerhard DM, Wohleb ES, Duman RS (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 .
PMC
4803609 .
PMID
26854424 .
^ Hashimoto K (October 2019).
"Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective" . Psychiatry and Clinical Neurosciences . 73 (10): 613–627.
doi :
10.1111/pcn.12902 .
PMC
6851782 .
PMID
31215725 .
^ Yaksh TL, Schwarcz R, Snodgrass HR (October 2017).
"Characterization of the Effects of L-4-Chlorokynurenine on Nociception in Rodents" . The Journal of Pain . 18 (10): 1184–1196.
doi :
10.1016/j.jpain.2017.03.014 .
PMID
28428091 .
External links
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