Research Project
6931786
DESCRIPTION (provided by applicant): Chronic pain is a major disorder affecting millions of Americans and costing the health community billions of dollars annually. While opiates are the drug of choice in treating acute pain, they have limited effectiveness, and have abuse and side effects issues that limit their use in treating chronic pain, especially neuropathic pain. A number of studies have indicated that NMDA receptor antagonists can produce analgesia and are effective in neuropathic pain animal models. However, direct acting NMDA receptor antagonists, in general, have been found to cause cognitive impairment in humans as well as other side effects that limit their therapeutic utility. NMDA receptors can also be blocked by inhibitors of the "GlyB" co-agonist site of the NMDA receptor, and glycine antagonists reduce hyperalgesia and allodynia in neuropathic pain models. Importantly, GlyB antagonists have fewer side effects than classic NMDA receptor antagonists, making them a safer alternative as analgesics. 7-Chlorokynurenic acid (7-C1-KYNA) is one of the most potent and specific GlyB antagonists known, and it has powerful anticonvulsant and neuroprotective actions in brain. However, like other glycine antagonists, 7-CI-KYNA doesn't easily penetrate the blood brain barrier. However, its prodrug, L-4-chlorokynurenine (4-CI-KYN), readily gains access to the brain following systemic administration and is efficiently converted to therapeutically relevant concentrations of 7-CI-KYNA. Therefore, 4-CI-KYN has unique properties that make it desirable in treating neuropathic pain; oral availability, it is preferentially converted to 7-CI-KYNA in brain areas that suffer neuronal injury and the site of greatest therapeutic need, and likely to have fewer negative side effects. VistaGen would like to develop 4-CI-KYN for the treatment of chronic pain. The goal of this Phase I SBIR grant is to produce sufficient preclinical efficacy data on the utility of 4-CI-KYN as an analgesic to support an IND application. This will be done by testing the effectiveness of 4-CI-KYN in established models of pain, including neuropathic pain.
