4-Chlorokynurenine

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, 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).

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 anticonvulsant effects in animal models of epilepsy, and depression, and has been found to activate dopaminergic neurons.

Currently-approved antidepressants, including commonly-prescribed selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), have limited effectiveness. 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.