Novel Methods to Identify Targets of the Neurological Agent (R)-Lacosamide

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DESCRIPTION (provided by applicant): Epilepsy and neuropathic pain are major neurological disorders that affect all populations. Pharmacological and clinical studies document the similarities in the pathophysiological phenomena observed in epilepsy and neuropathic pain, and thus an increasing number of seizure medications are used for both disorders. Unfortunately, many patients continue to have seizures and experience pain while others experience disturbing side-effects. There is a need, therefore, for new, efficacious agents that target novel neurological pathways for these disorders. (R)-Lacosamide ((R)-2) is a simple, stereospecific agent that we discovered in 1992; it has entered phase III clinical trials for the treatment of partial seizures and diabetic neuropathy in the United States and Europe. The pharmacological profile for (R)-2 is distinct from all established antiepileptic agents. Preliminary pharmacological studies indicate that (R)-2 exerts its activity by multiple pathways. Efforts (e.g., electrophysiology, radioligand displacement assays) to identify the sites of (R)-2 function have been unsuccessful. This proposal focuses on elucidating the (R)-2 binding sites in the brain. Powerful methods are employed to address this objective. We advance a series of lacosamide analogs termed affinity bait (AB), chemical receptor (CR), and affinity bait and chemical receptor (AB&CR) designed to capture and identify the targets. We couple our molecular probes with mRNA-display and affinity-based technologies to reveal (R)-2 binding sites that explicate function. The targets are characterized and validated, and the molecular sites of (R)-2 binding determined. The use of AB&CR probes with mRNA-display and affinity matrix methods as a novel tool expands the use of these technologies for ligand site identification, where binding is modest and where moderate-to- extensive ligand structural change abolishes target binding. Relevance to public health: Current medications for the treatment of epilepsy are ineffective for approximately one-third of patients. The situation is comparable for neuropathic pain management. (R)-2's pharmacological profile is novel, but its molecular targets are unknown. Delineation of these sites will provide a basis for understanding the mechanism of (R)-2 function and maximizing its therapeutic potential and may provide new information for the control of both neurological disorders.