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NS 1209 (SPD-502) (Figure 3) is an antagonist of AMPA and glutamate receptor 5 (GluR5) receptors. It is under development for the potential treatment of status epilepticus and other types of seizures.

6.11.6.3.4 Retigabine

Retigabine (Figure 3) is a carbamic acid ethyl ester that is thought to act as a selective potassium channel opener, for the potential treatment of complex partial seizures.

6.11.6.3.5 Talampanel

Talampanel (Figure 3) reduces seizure frequency in humans and is effective against PTZ, aminophylline, and MES induced seizures in rodents. It is a selective noncompetitive AMPA receptor antagonist.

E 2007 (structure unavailable) is a selective, noncompetitive AMPA receptor antagonist which in addition to its anticonvulsant activity is being examined for its potential utility in the treatment of migraine, Parkinson's disease, and multiple sclerosis.

6.11.6.3.7 Lacosamide

Lacosamide (also known as harkoseride and erlosamide) (Figure 3) is a propioamide under development as an oral agent for the potential treatment of epilepsy. While it is rumored to act through a distinct site in the CNS, like other AEDs, it has polypharmic actions with inhibition of NMDA receptor function and potentiation of GABAergic transmission. It is predicted, based on activity in animal models, to be useful in the treatment of partial onset and generalized tonic-clonic seizures. It is also being evaluated for its utility in the treatment of neuropathic pain.

6.11.6.3.8 Safinamide

Safinamide (NW-1015) (Figure 3) had its origins in the weak AED, milacemide. Safinamide is a broad-spectrum AED, effective in the treatment of partial and generalized seizures in humans, producing its effects via a combination of ion channel-related activities including sodium channel blockade (IC50 = 8 mM), calcium channel modulation, and glutamate release inhibition. It is also a potent MAO-B inhibitor (IC50 = 100 nM), with some effects of a dopamine uptake inhibitor. In this latter context, it is in phase III trials for the treatment of Parkinson's disease (see 6.08 Neurodegeneration).

6.11.6.3.9 Remacemide

Remacemide (Figure 3) has been used as add-on therapy in refractory epilepsy. Mechanistically, it is a low-affinity NMDA receptor antagonist. In animals it blocks MES, NMDA, cocaine, 4-aminopyridine and kainic acid induced seizures but has no effect on picrotoxin-, bicuculline-, or strychnine-induced seizures.

6.11.6.3.10 Losigamone

Losigamone (Figure 3) is a novel AED with modest anticonvulsant activity. It is more potent than phenytoin or VPA in the MES test in mice. The mechanism of action is unknown but involves indirect activation of GABA-dependent chloride channels.

6.11.6.3.11 Second-generation valproic acid analogs

With the successful use of VPA not only as an broad-spectrum AED but also in the treatment of bipolar affective disorder (BAPD), a number of VPA analogs (Figure 4) have been under investigation as NCEs. These include: ABS-103, NPS-1776, TVP-1901 (valrocemide) (Figure 4), and the VPA prodrug, DP-VPA (Figure 4). While all have been phenotypically evaluated in animal models of epilepsy, given the predictivity of these models for the human situation, these agents may have considerable potential in BAPD and migraine, both larger and less genericized markets than epilepsy. To date, these NCEs, all closely related in structure to VPA, have moved slowly through the development process, with questionable if any improvements over efficacy and side effect liability profiles to VPA. ABT-769 (Figure 4)36 is a newly synthesized VPA analog that has broad-spectrum anticonvulsant activity with a similar efficacy profile to VPA but an improved safety profile in terms of neither inducing neural tube defects nor affecting mitochondrial fatty acid b-oxidation, the latter related to the hepatotoxic effects of the 4-ene and 2,4-diene metabolites of VPA.

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