Talampanel

Howes, John F.; Bell, Cynthia

doi:10.1016/j.nurt.2006.11.001

Cited by 64 publications

(55 citation statements)

References 21 publications

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“…Indeed, AMPA receptor antagonists have shown efficacy in animal models of cerebral ischemia and in seizure reduction in clinical trials (49). By analogy, compounds that antagonize the interaction between TARPs and AMPA receptors should down-regulate strong depolarizing responses and could be useful in excitotoxic processes.…”

Section: Discussionmentioning

confidence: 99%

AMPA receptors and stargazin-like transmembrane AMPA receptor-regulatory proteins mediate hippocampal kainate neurotoxicity

Tomita

Byrd²,

Rouach

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Naturally occurring glutamate analogs, such as kainate and domoate, which cause excitotoxic shellfish poisoning, induce nondesensitizing responses at neuronal ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In addition to acting on AMPA receptors, kainate and domoate also activate high-affinity kainate-type glutamate receptors. The receptor type that mediates their neurotoxicity remains uncertain. Here, we show that the transmembrane AMPA receptor-associated protein (TARP) ␥-2 (or stargazin) and the related TARP ␥-8 augment responses to kainate and domoate by making these neurotoxins more potent and more efficacious AMPA receptor agonists. Genetic deletion of hippocampal enriched ␥-8 selectively abolishes sustained depolarizations in hippocampus mediated by kainate activation of AMPA receptors. ␥-8 knockout mice display typical kainate-induced seizures; however, the associated neuronal cell death in the hippocampus is attenuated in mice lacking ␥-8. This work decisively demonstrates that TARP-associated AMPA receptors mediate kainate neurotoxicity and identifies TARPs as targets for modulating neurotoxic properties of AMPA receptors.excitotoxicity ͉ epilepsy ͉ PSD-95 ͉ synapse T he ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptors are selective cation channels and mediate most of the postsynaptic depolarization that induces neuronal firing. Dynamic trafficking of neuronal AMPA receptor proteins participates in the plasticity of synaptic transmission that underlies aspects of learning and memory. AMPA receptor channels comprise heterotetramers of subunits GluR1-4, and each subunit can be alternatively spliced as either a flip or flop form (1, 2). The distinct expression of these AMPA receptor subunits and alternatively spliced isoforms in discrete neuronal populations helps determine differential AMPA receptor function and synaptic plasticity throughout the brain (3-7).Neuronal AMPA receptors also contain transmembrane AMPA receptor-regulatory protein (TARP) auxiliary subunits (8). The TARP family comprises five isoforms: ␥-2 (or stargazin), ␥-3, ␥-4, ␥-7, and ␥-8, which are predominantly expressed in adult cerebellum, adult cerebral cortex, early developmental brain, cerebellar Purkinje cells, and adult hippocampus, respectively (9, 10). Stargazer mice, which show absence epilepsy and cerebellar ataxia, have a genetic mutation in stargazin, the prototypical TARP (11). Physiological studies have shown that cerebellar granule cells from stargazer mice selectively lack functional AMPA receptors (12). Biochemical and cell biological studies have shown that stargazin binds to AMPA receptors and traffics the receptors to the neuronal cell surface (13,14). Interaction of stargazin with the postsynaptic density-95 and related proteins (15) mediates synaptic clustering of AMPA receptors (16,17). Stargazin also cooperates with postsynaptic density-95 to control synaptic plasticity (18)(19)(20). In addition to trafficking AMPA receptors, stargazin modulates th...

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Section: Discussionmentioning

confidence: 99%

AMPA receptors and stargazin-like transmembrane AMPA receptor-regulatory proteins mediate hippocampal kainate neurotoxicity

Tomita

Byrd²,

Rouach

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Talampanel (GYKI 53773, LY300164; Howes and Bell, 2007) and perampanel (E2007) are noncompetitive antagonists that are highly selective for AMPA over other glutamate receptors. Talampanel demonstrated efficacy in phase II trials in patients with refractory partial seizures (Chappell et al, 2002), and perampanel is under study.…”

Section: B the Next Generation ␣-Amino-3-hydroxy-5-methyl-4-isoxazolmentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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“…Moreover, the anticonvulsant effects of compound 6d were comparable to those of active 2,3-benzodiazepine derivatives CFM-2 and talampanel, which has already undergone phase 1 and 2 trials for refractory epilepsy, as well as amyotrophic lateral sclerosis and Parkinson disease. 21,22) It is interesting to note that in this experimental model of epilepsy the observed activity of compound 6d exceeded that of valproate and gabapentin, two drugs largely used in antiepileptic therapy. On the basis of calculation of Log D 7.4 , 26) predicted from a commercially available program (advanced chemistry development/Lab), we hypothesized that the hydrophobic character of methyl substituent could positively contribute to the blood-brain barrier crossing thus improving the anticonvulsant efficacy.…”

Section: Resultsmentioning

confidence: 84%

“…1). 17,21,22) Starting from the "lead compound" 1, in several previous studies, we examined a large series of its analogues and reported a comprehensive structure-active relationship (SAR) studies concerning the influence of specific substituents on tetrahydroisoquinoline skeleton; we found that the most active derivatives are generally characterized by the presence of 2-acetyl substituent; moreover two methoxy substituents on the benzene fused ring are crucial to produce pharmacological effects.19) Furthermore our investigations suggested that the introduction of hydrophobic substituents at 4Ј-position of C-1 phenyl moiety (e.g. halogen atoms) could improve the anticonvulsant efficacy against sound-induced seizures in Dilute Brown non-Agouti (DBA/2) mice.…”

mentioning

confidence: 99%

Synthesis and Structure-Active Relationship of 1-Aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Anticonvulsants

Gitto

Luca

Ferro

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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Epilepsy is commonly considered the result of an imbalance between excitatory and inhibitory "tone" leading to periodic and unpredictable seizures related to an abnormal discharge of cerebral neurons. Epilepsy is one of the most common neurological disorders, affecting ca. 1% of the population worldwide, and the incidence increases to 3% by the age of 75 years. Although most people become seizure-free with drug therapy, there is still a significant number of patients (30%) who are resistant to the currently available antiepileptic drugs whether used alone or in combination. The pathophysiology of epilepsy is complex and several mechanisms play a role in epileptogenesis and epileptogenicity.1) The efficacy of anticonvulsant drugs may be connected with different molecular targets to reduce the excitability of neurons involved in seizure onset.2) The mechanism of action of currently available effective antiepileptics are: a) the induction of a prolonged inactivation of the Na ϩ channel; b) the blockade of Ca 2ϩ channel currents; c) the enhancement of the inhibitory g-aminobutyrate (GABA)ergic neurotransmission or the modulation of excitatory glutamatergic neurotransmission.3) With respect to this last pharmacological target, extensive studies have demonstrated that competitive and noncompetitive antagonists of the ionotropic glutamate receptors (iGluRs) show promise in terms of their therapeutic potential for the prevention and treatment of the epilepsy. [3][4][5][6][7][8][9][10] In our previous works, some isoquinoline derivatives were found to have anticonvulsant activities in various seizure models interacting with glutamate ionotropic a-amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA) receptor (AMPAR) subtype in a selective and non-competitive fashion. [11][12][13][14][15][16][17][18][19][20] The most active compound of the series was the 2-acetyl-1-(4Ј-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1, Fig. 1) which showed both in in vivo and in vitro tests activity stronger than other known AMPAR antagonists such as GYKI 52466, talampanel, and CFM-2 (Fig. 1). 17,21,22) Starting from the "lead compound" 1, in several previous studies, we examined a large series of its analogues and reported a comprehensive structure-active relationship (SAR) studies concerning the influence of specific substituents on tetrahydroisoquinoline skeleton; we found that the most active derivatives are generally characterized by the presence of 2-acetyl substituent; moreover two methoxy substituents on the benzene fused ring are crucial to produce pharmacological effects.19) Furthermore our investigations suggested that the introduction of hydrophobic substituents at 4Ј-position of C-1 phenyl moiety (e.g. halogen atoms) could improve the anticonvulsant efficacy against sound-induced seizures in Dilute Brown non-Agouti (DBA/2) mice. These experimental evidences were confirmed by our computational studies in which we developed a 3-D pharmacophore model for noncompetitive AMPAR antagonists.15) Herein we report the sy...

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Talampanel

Cited by 64 publications

References 21 publications

AMPA receptors and stargazin-like transmembrane AMPA receptor-regulatory proteins mediate hippocampal kainate neurotoxicity

AMPA receptors and stargazin-like transmembrane AMPA receptor-regulatory proteins mediate hippocampal kainate neurotoxicity

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Synthesis and Structure-Active Relationship of 1-Aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Anticonvulsants

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