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. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Fureman, Brandy E
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University of North Carolina Chapel Hill
Schools of Pharmacy
Chapel Hill
United States
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Park, Ki Duk; Yang, Xiao-Fang; Lee, Hyosung et al. (2013) Discovery of lacosamide affinity bait agents that exhibit potent voltage-gated sodium channel blocking properties. ACS Chem Neurosci 4:463-74
Wang, Yuying; Wilson, Sarah M; Brittain, Joel M et al. (2011) Merging Structural Motifs of Functionalized Amino Acids and ?-Aminoamides Results in Novel Anticonvulsant Compounds with Significant Effects on Slow and Fast Inactivation of Voltage-gated Sodium Channels and in the Treatment of Neuropathic Pain. ACS Chem Neurosci 2:317-322
Park, Ki Duk; Kim, Dongwook; Reamtong, Onrapak et al. (2011) Identification of a lacosamide binding protein using an affinity bait and chemical reporter strategy: 14-3-3 ?. J Am Chem Soc 133:11320-30
Wang, Yuying; Park, Ki Duk; Salome, Christophe et al. (2011) Development and characterization of novel derivatives of the antiepileptic drug lacosamide that exhibit far greater enhancement in slow inactivation of voltage-gated sodium channels. ACS Chem Neurosci 2:90-106
Morieux, Pierre; Salome, Christophe; Park, Ki Duk et al. (2010) The structure-activity relationship of the 3-oxy site in the anticonvulsant (R)-N-benzyl 2-acetamido-3-methoxypropionamide. J Med Chem 53:5716-26
Salome, Christophe; Salome-Grosjean, Elise; Stables, James P et al. (2010) Merging the structural motifs of functionalized amino acids and alpha-aminoamides: compounds with significant anticonvulsant activities. J Med Chem 53:3756-71
Salome, Christophe; Salome-Grosjean, Elise; Park, Ki Duk et al. (2010) Synthesis and anticonvulsant activities of (R)-N-(4'-substituted)benzyl 2-acetamido-3-methoxypropionamides. J Med Chem 53:1288-305
Park, Ki Duk; Stables, James P; Liu, Rihe et al. (2010) Proteomic searches comparing two (R)-lacosamide affinity baits: An electrophilic arylisothiocyanate and a photoactivated arylazide group. Org Biomol Chem 8:2803-13
Salomé, Christophe; Kohn, Harold (2009) Triphenylphosphine Dibromide: A Simple One-pot Esterification Reagent. Tetrahedron 65:456-460
Park, Ki Duk; Morieux, Pierre; Salomé, Christophe et al. (2009) Lacosamide isothiocyanate-based agents: novel agents to target and identify lacosamide receptors. J Med Chem 52:6897-911

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