Investigational antidepressant compound
Pharmaceutical compound
L -4-Chlorokynurenine4-Cl-KYN ; developmental code nameAV-101 ) is an orally active small molecule prodrug of7-chlorokynurenic acid , aNMDA receptor antagonist . It was investigated as a potential rapid-actingantidepressant .
AV-101 was discovered atMarion Merrell Dow and its biological activity was explored atUniversity of Maryland . It underwent initial development at Artemis Neuroscience which was acquired by VistaGen in 2003. A phase IIclinical trial failed to show any effect over placebo in alleviatingtreatment-resistant depression .[ 1]
Stylized depiction of an activated NMDAR. Glutamate is in the glutamate-binding site and glycine is in the glycine-binding site.[ 2] 4-Chlorokynurenine penetrates theblood–brain barrier via thelarge neutral amino acid transporter 1 .[ 3] central nervous system it is converted to 7-chlorokynurenic acid bykynurenine aminotransferase inastrocytes .[ 4]
Most of its therapeutic potential is believed to occur via 7-chlorokynurenic acid which inhibits the glycine co-agonist site ofNMDA receptors .[ 4]
Anothermetabolite , 4-chloro-3-hydroxy-anthranilic acid, inhibits the enzyme3-hydroxyanthranilate oxidase , which provides a rationale for further testing in neurodegenerative diseases.[ 4]
4-Chlorokynurenine is prodrug of7-chlorokynurenic acid (7-Cl-KYNA), which in turn is a halogenated derivative ofL -kynurenine .[ 4]
Artemis Neuroscience was formed to develop work done by University of Maryland professor Robert Schwartz in collaboration with scientists atMarion Merrell Dow (which became part ofSanofi 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 anInvestigational New Drug application with the FDA for use of AV-101 inneuropathic pain in 2013.[ 4]
In 2013, otherNMDA receptor antagonists in clinical trials for depression includedlanicemine ,esketamine , andrapastinel , with lanicemine being the most advanced.[ 9]
By 2013, AV-101 had successfully gone through two Phase I clinical trials.[ 4] major depression .[ 10] [ 1] [ 11]
Preclinical studies inanimal models suggested efficacy in treating neuropathic pain.[ 12] Huntington's disease [ 4] ketamine inbehavioral models of depression in rodents.[ 10]
^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 fromthe original on January 13, 2017. RetrievedJanuary 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, 2011.8-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 .
SSRIs Tooltip Selective serotonin reuptake inhibitors SNRIs Tooltip Serotonin–norepinephrine reuptake inhibitors NRIs Tooltip Norepinephrine reuptake inhibitors NDRIs Tooltip Norepinephrine–dopamine reuptake inhibitors NaSSAs Tooltip Noradrenergic and specific serotonergic antidepressants SARIs Tooltip Serotonin antagonist and reuptake inhibitors SMS Tooltip Serotonin modulator and stimulators Others
TCAs Tooltip Tricyclic antidepressants TeCAs Tooltip Tetracyclic antidepressants Others
Non-selective MAOA Tooltip Monoamine oxidase A -selectiveMAOB Tooltip Monoamine oxidase B -selective
AMPAR Tooltip α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor KAR Tooltip Kainate receptor NMDAR Tooltip N-Methyl-D-aspartate receptor
Transporter
EAATs Tooltip Excitatory amino acid transporters vGluTs Tooltip Vesicular glutamate transporters
Enzyme
GAH Tooltip Glutamine aminohydrolase (glutaminase) AST Tooltip Aspartate aminotransferase ALT Tooltip Alanine aminotransferase GDH Tooltip Glutamate dehydrogenase GS Tooltip Glutamine synthetase GAD Tooltip Glutamate decarboxylase
