? ? Epilepsy affects over 2.5 million people in the US, and over 180,000 new cases of the disease are diagnosed each year. Nearly half of the people suffering from epilepsy are not effectively treated. Moreover, currently used anticonvulsants can cause significant side effects, which often interfere with compliance. Clearly, there is a need for new, safer drugs to treat epilepsy. Glutamate, by stimulating NMDA receptors, has been implicated in the neuropathology and clinical symptoms of epilepsy, and NMDA receptor antagonists are potent anticonvulsants. Antagonists at the GlyB co-agonist site inhibit NMDA receptor function and are also anticonvulsant. Importantly, GlyB antagonists have fewer side effects than classic NMDA receptor antagonists and other antiepileptic agents, making them a safer alternative to available anticonvulsant medications. 7-Chlorokynurenic acid (7-C1-KYNA) is one of the most potent and specific GlyB antagonists currently known and is a powerful anticonvulsant when injected into the brain. However, like almost all GlyB antagonists developed so far, 7-C1-KYNA crosses the blood-brain barrier very poorly and is therefore ineffective following peripheral administration. Its pro-drug, L-4-chlorokynurenine (4-C1-KYN), on the other hand, readily gains access to the brain. Following systemic administration, 4-C1-KYN is efficiently converted to 7-C1-KYNA and prevents seizures in animal models of epilepsy. 7-C1-KYNA formation occurs preferentially in brain areas that suffer seizure-related brain injury, thereby reducing the risk for side effects with chronic use. Furthermore, 4-C1-KYN forms a second metabolite, which blocks the synthesis of the proconvulsant quinolinic acid in brain. These unique properties make 4-C1-KYN a highly innovative candidate for the treatment of epilepsy. The project proposed here by Vistagen will advance the preclinical development of 4-C1-KYN as a treatment for adult and childhood epilepsy. We will conduct extensive pharmacokinetic and ADME analyses to further delineate the oral bioavailability of the drug observed in pilot studies, will subject 4-C1-KYN to a battery of safety and toxicology studies and will test anticonvulsant efficacy of the compound in two chronic animal models of epilepsy, CLE and kindling. Finally, we will begin to develop the protocols needed to submit an IND for FDA approval to conduct clinical testing of the drug in humans as a new and improved anti-epileptic agent. ? ? ?
