This research project aims at identifying the biological targets of the neurological agent (R)-lacosamide (LCM). (R)-LCM is a potent anti-epileptic agent emerging from Phase III clinical trials for the treatment of epilepsy and neuropathic pain. The pharmacological studies document that LCM has a unique profile of activity that differentiates it from known anti-epileptic agents. Based on these findings, we hypothesize that (R)-LCM binds to different proteins, with low to modest affinity. The understanding of LCM's mechanism of action(s) will help increase our understanding of seizure and pain disorders, and permit the rational development of new clinical agents. Our first specific aim is the design and synthesis of molecular probes derived from (R)-LCM termed Affinity Bait (AB), Chemical Reporter (CR), and AB&CR. These agents will be evaluated for anticonvulsant activity in animal models at the NINDS Anticonvulsant Screening Project. In the second specific aim, we use the LCM AB&CR agents to examine a select panel of proteins, which constitute relevant targets for (R)-LCM. Our third specific aim utilizes the AB&CR agents to identify the (R)-LCM protein targets in the mouse brain using an affinity-based approach. Finally, in the last specific aim we interrogate the mouse brain proteome using mRNA display and the LCM AB&CR agents for sites of drug function.
Specific Aim 4 will be conducted by the Liu laboratory at UNC-Chapel Hill. Central to all our biological studies are the construction of the LCM AB&CR agents that covalently modify the target through the AB group and then are removed from the biological mixture via the CR group and a bioorthogonal probe. Though still unknown, the mechanism of action of the anti-epileptic agent (R)-lacosamide has been shown to differ from other anticonvulsant drugs. The identification of lacosamide drug targets will provide us important, new information of the biological mechanisms underlying epilepsy and neuropathic pain. This knowledge will allow the rational development of new anti-epileptic and neuropathic pain agents.
| 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; 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; 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 |
| Morieux, Pierre; Stables, James P; Kohn, Harold (2008) Synthesis and anticonvulsant activities of N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide derivatives. Bioorg Med Chem 16:8968-75 |
