4-chloro-kynurenine + probenecid

4-chloro-kynurenine + probenecid is an experimental **oral combination therapy** designed to increase the central nervous system (CNS) availability of 7-chloro-kynurenic acid, a **NMDA receptor glycine site antagonist**. **4-chloro-kynurenine (4-Cl-KYN)** is a prodrug that crosses the blood-brain barrier via the large neutral amino acid transporter 1 (LAT1), where it is converted to 7-chloro-kynurenic acid (7-Cl-KYNA), the active agent that antagonizes the glycine site of NMDA receptors. However, 7-Cl-KYNA is rapidly transported out of the brain by probenecid-sensitive organic anion transporters (OAT1/3, MRP4). **Probenecid**, an inhibitor of these transporters, is coadministered to dramatically increase CNS levels of 7-Cl-KYNA, shown to produce up to an 885-fold increase in preclinical studies. The combination is being investigated for **major depressive disorder**, especially treatment-resistant depression, and has additional potential for L-DOPA-induced dyskinesia, neuropathic pain, and seizures. Clinical development is ongoing to evaluate whether this strategy overcomes the lack of efficacy seen with 4-Cl-KYN monotherapy in prior trials.[2][3][4][7]

Other names

L-4-chlorokynurenine + probenecid