A crossover, add-on trial of talampanel in patients with refractory partial seizures

Chappell, Amy S.; Sander, Josemir W.; Brodie, M.J.; Chadwick, D.; Lledó, Alberto; Zhang, Dingguo; Bjerke, J.S.; Kiesler, G.M.; Arroyo, Santiago

doi:10.1212/wnl.58.11.1680

Cited by 86 publications

(65 citation statements)

References 7 publications

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“…A third compound, the competitive AMPA/kainate receptor antagonist NS1209 has been studied in status epilepticus but the results have not been made available (64). In a small adjunctive trial in patients with refractory partial seizures, orally-administered talampanel appeared to show efficacy (65). However, because of pharmacokinetic interactions (talampanel plasma concentrations are markedly reduced in the presence of enzyme-inducing AEDs), the results were inconclusive.…”

Section: Human Studies With Ampa Receptor Antagonists In the Treatmenmentioning

confidence: 99%

Revisiting AMPA Receptors as an Antiepileptic Drug Target

2011

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AMPA receptors are ion channels localized to excitatory synapses in the central nervous system that mediate fast (millisecond time scale) excitatory neurotransmission ( Fig. 1) (1). In excitatory neurons, action potentials evoke the release of glutamate from presynaptic terminals at synapses onto postsynaptic excitatory and inhibitory neurons. Synapses onto excitatory neurons are predominantly located on dendritic spines whereas excitatory synapses onto inhibitory interneurons are located on the aspiny dendritic shafts typical of these cells (2, 3). In either case, the glutamate released from the excitatory neuron axon terminals diffuses across the synaptic cleft and binds to AMPA receptors in the postsynaptic membrane. The AMPA receptors are large multisubunit protein complexes that span the membrane and have an ion-selective central pore that in the absence of glutamate is closed to ion flow. Binding of glutamate causes the AMPA receptors to gate open, which allows cations to flux across the postsynaptic membrane, resulting in a brief depolarization known as the excitatory postsynaptic potential (EPSP). Although AMPA receptors are permeable to sodium, potassium and in some cases also calcium, at resting potential sodium is the main carrier of the depolarizing current. Summation of EPSPs leads to the firing of action potentials by the postsynaptic neuron, completing the transmission of the synaptic signal. Given their role in fast excitatory signaling in the brain, AMPA receptors are a critical component of all neuronal networks. AMPA receptors are as fundamental to brain function as sodium channels but it is important to appreciate the distinction between the two. AMPA receptors mediate synaptic signaling whereas sodium channels are responsible for a neuron's intrinsic excitability. In line with their distinct functions, sodium channels are voltage-gated and they open in response to membrane depolarization. In contrast, AMPA receptors are largely insensitive to membrane potential; as neurotransmitter-gated channels, their opening is controlled by a chemical signal -glutamate, the universal chemical messenger for fast excitatory neurotransmission. The Architecture of AMPA ReceptorsThe cloning of the first AMPA receptor subunit in 1989 enabled the structural analysis of AMPA receptors and a detailed characterization of their physiology and pharmacology (4). It is now well established that there are four AMPA receptor subunits designated GluA1-GluA4 (formerly GluR1-GluR4), each encoded by a separate gene (5). The subunits have a modular organization (Fig. 2) (6, 7). There is a large extracellular aminoterminal domain that is involved in receptor assembly, trafficking and modulation; a ligand-binding domain that serves as the recognition site for agonists (including the natural agonist glutamate) and also represents the binding site for competitive antagonists; a transmembrane domain that forms the ion channel (consisting of three membrane-spanning hydrophobic domains and one intramembranous reentrant loop); and a...

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Section: Human Studies With Ampa Receptor Antagonists In the Treatmenmentioning

confidence: 99%

Revisiting AMPA Receptors as an Antiepileptic Drug Target

2011

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“…One 2,3-benzodiazepine, talampanel (GYKI 53773; LY300164), has shown efficacy in clinical trials. 262,263 Nonetheless, it is unclear whether AMPA receptor antagonists will be tolerable at therapeutic doses. In animal models, such agents generally cause neurological impairment at doses near those that confer seizure protection.…”

Section: Ionotropic Glutamate Receptorsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…Both GYKI 53405 and talampanel are protective in the MES test in mice and also in various chemoconvulsant models, but only at doses near those that cause motor side effects (Andrási, 2001). In clinical trials talampanel has been reported to be well tolerated, but sedation may occur, especially with initial dosing (Chappell et al, 2002;Langan et al, 2003;Danielsson et al, 2004).…”

Section: Ampa Receptor Antagonistsmentioning

confidence: 99%

Diverse mechanisms of antiepileptic drugs in the development pipeline

2006

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There is a remarkable array of new chemical entities in the current antiepileptic drug (AED) development pipeline. In some cases, the compounds were synthesized in an attempt improve upon the activity of marketed AEDs. In other cases, the discovery of antiepileptic potential was largely serendipitous. Entry into the pipeline begins with the demonstration of activity in one or more animal screening models. Results from testing in a panel of such models provide a basis to differentiate agents and may offer clues as to the mechanism. Target activity may then be defined through cellbased studies, often years after the initial identification of activity. Some pipeline compounds are believed to act through conventional targets, whereas others are structurally novel and may act by novel mechanisms. Follow-on agents include the levetiracetam analogs brivaracetam and seletracetam that act as SV2A-ligands; the valproate-like agents valrocemide, valnoctamide, propylisopropyl acetamide, and isovaleramide; the felbamate analog flurofelbamate, a dicarbamate, and the unrelated carbamate RWJ-333369; the oxcarbazepine analog licarbazepine, which probably acts as a use-dependent sodium channel blockers, and its prodrug acetate BIA 2-093; and various selective partial benzodiazepine receptor agonists, including ELB139, which is a positive allosteric modulator of α3-containing GABA A receptors. A variety of AEDs that may act through novel targets are also in clinical development: lacosamide, a functionalized amino acid; talampanel, a 2,3-benzodiazepine selective noncompetitive AMPA receptor antagonist; NS1209, a competitive AMPA receptor antagonist; ganaxolone, a neuroactive steroid that acts as a positive modulator of GABA A receptors; retigabine, a KCNQ potassium channel opener with activity as a GABA A receptor positive modulator; the benzanilide KCNQ potassium channel opener ICA-27243 that is more selective than retigabine; and rufinamide, a triazole of unknown mechanism.

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A crossover, add-on trial of talampanel in patients with refractory partial seizures

Cited by 86 publications

References 7 publications

Revisiting AMPA Receptors as an Antiepileptic Drug Target

Revisiting AMPA Receptors as an Antiepileptic Drug Target

Molecular Targets for Antiepileptic Drug Development

Diverse mechanisms of antiepileptic drugs in the development pipeline

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