New non competitive AMPA antagonists

Ábrahám, Gizella; Sólyom, Sándor; Csuzdi, Emese; Berzsenyi, Pál; Ling, István; Tarnawa, Istvàn; Hámori, Tamás; Pallagi, István; Horváth, Katalin; Andrási, F; Kapus, Gábor; Hársing, László G.; Király, István; Patthy, Miklós; Horváth, Gyula

doi:10.1016/s0968-0896(00)00133-4

Cited by 53 publications

(25 citation statements)

References 43 publications

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“…In a previous report (Noda et al, 2000), RT-PCR study suggested that rat microglia might also express KA-type Glu receptors. Using KA as an agonist of AMPA/KA type of Glu receptor, which gave noninactivating inward currents, we introduced the specific inhibitor of AMPA-type Glu receptors, LY300164, which corresponds to GYKI53773 and a noncompetitive antagonist of AMPA receptor-mediated responses (Czuczwar et al, 1998;Abraham et al, 2000). In our study, the sustained inward current in the presence of 300 M KA was completely inhibited by 100 M LY300164 in five cells tested (Fig.…”

Section: Discussionmentioning

confidence: 69%

Heterogeneity and potentiation of AMPA type of glutamate receptors in rat cultured microglia

Hagino

Kariura

Manago

et al. 2004

Glia

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alpha-amino-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor in rat cultured microglia were analyzed precisely using flop- and flip-preferring allosteric modulators of AMPA receptors, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide (PEPA) and cyclothiazide (CTZ), respectively. Glutamate (Glu)- or kainite (KA)-induced currents were completely inhibited by a specific blocker of AMPA receptor, LY300164, indicating that functional Glu-receptors in cultured microglia are mostly AMPA receptor but not KA receptor in many cells. Glu- and KA-induced currents were potentiated by PEPA and CTZ in a concentration-dependent manner. The ratio of the potentiation by PEPA to the potentiation by cyclothiazide varied with cells between 0.1 and 0.9, suggesting cell-to-cell heterogeneity of AMPA receptor subunits expressed in microglia. Quantitative RT-PCR revealed that GluR1-3 mainly occurred in the flip forms, which agreed with the stronger potentiation of receptor currents by CTZ vs. PEPA. Finally, the potentiation of microglial AMPA receptors by PEPA and CTZ inhibited the Glu-induced release of tumor necrosis factor-alpha (TNF-alpha) unpredictably. The increase in TNF-alpha release by Glu or KA required extracellular Na+ and Ca2+ ions but not mitogen-activated protein kinase (MAPK), suggesting the effects of PEPA and CTZ were not due to the inhibition of MAPK. These results suggest that potentiation of microglial AMPA receptors serves as a negative feedback mechanism for the regulation of TNF-alpha release and may contribute to the ameliorating effects of allosteric modulators of AMPA receptors.

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Section: Discussionmentioning

confidence: 69%

Heterogeneity and potentiation of AMPA type of glutamate receptors in rat cultured microglia

Hagino

Kariura

Manago

et al. 2004

Glia

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“…It remains to be determined why interaction with this binding site has the stronger effect on ADDL binding to neurons. The GYKI class AMPAR antagonists are neuroprotective in a variety of animal disease models (70,71,73,74). As increased epileptiform activities develop in transgenic mice, presumably because of accumulated A␤ levels in the brain (75), it will be important to determine whether GYKI25466 can protect AD transgenic mice through its inhibitory effect of ADDL binding-AMPAR interaction, which if true would offer a potential approach for treating the neuronal dysfunction and cognitive deficits in AD.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Calcineurin-mediated Endocytosis and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Prevents Amyloid β Oligomer-induced Synaptic Disruption

Zhao

Santini

Breese

et al. 2010

Journal of Biological Chemistry

173

170

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Synaptic degeneration, including impairment of synaptic plasticity and loss of synapses, is an important feature of Alzheimer disease pathogenesis. Increasing evidence suggests that these degenerative synaptic changes are associated with an accumulation of soluble oligomeric assemblies of amyloid ␤ (A␤) known as ADDLs. In primary hippocampal cultures ADDLs bind to a subpopulation of neurons. However the molecular basis of this cell type-selective interaction is not understood. Here, using siRNA screening technology, we identified ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits and calcineurin as candidate genes potentially involved in ADDL-neuron interactions. Immunocolocalization experiments confirmed that ADDL binding occurs in dendritic spines that express surface AMPA receptors, particularly the calcium-impermeable type II AMPA receptor subunit (GluR2). Pharmacological removal of the surface AMPA receptors or inhibition of AMPA receptors with antagonists reduces ADDL binding. Furthermore, using co-immunoprecipitation and photoreactive amino acid cross-linking, we found that ADDLs interact preferentially with GluR2-containing complexes. We demonstrate that calcineurin mediates an endocytotic process that is responsible for the rapid internalization of bound ADDLs along with surface AMPA receptor subunits, which then both colocalize with cpg2, a molecule localized specifically at the postsynaptic endocytic zone of excitatory synapses that plays an important role in activity-dependent glutamate receptor endocytosis. Both AMPA receptor and calcineurin inhibitors prevent oligomer-induced surface AMPAR and spine loss. These results support a model of disease pathogenesis in which A␤ oligomers interact selectively with neurotransmission pathways at excitatory synapses, resulting in synaptic loss via facilitated endocytosis. Validation of this model in human disease would identify therapeutic targets for Alzheimer disease. Alzheimer disease (AD)2 likely begins with deficits in synaptic transmission in brain regions that are critical for higher cognitive function (1), as stereological analyses of post-mortem samples show that synaptic loss correlates with cognitive dysfunction better than amyloid plaque or neurofibrillary tangle load (2-5). One of the triggers for such synaptic impairments is thought to be soluble oligomers of amyloid ␤ (A␤) peptides that accumulate in the brain and are potently toxic to synapses (6 -8). A␤ synaptotoxicity is consistently observed with A␤ oligomers from synthetic preparations (9 -11), cell-derived forms (7,8,12), and the brains of AD patients (13) and APPswe transgenic mice (14), such that these oligomers disrupt synaptic structure (9, 10, 15-18), inhibit long term potentiation (LTP) (7,8,19), and induce memory deficits (13,20).Although the mechanisms by which A␤ oligomers disrupt synaptic function are not known, A␤ oligomers bind to the dendritic processes of specific subtypes of hippocampal neurons with high affinity (9,15,21), leading to the hypothesi...

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“…Both models contain two donor sites, a donor atom, and a hydrophobic center. The two models differ at one of the donor sites: in type 1 pharmacophore model, this site can be represented by, for example, the lone pair of electrons of the N-3 atom in GYKI 52466 (see its chemical structure in Figure 1); in type 2 model, this donor site can be defined by, for example, the lone pair of electrons from a heteroatom of heterocycles, such as GYKI 47261 [6-(4-aminophenyl)-8-chloro-2-methyl-11H-imidazo- [1,2c] [2,3]benzodiazepine] 19 and some azolo-condensed 2,3-BDZs. 18 Based on favorable inhibitory properties of these earlier compounds, Rezessy and Soĺyom 18 proposed that heterocycles at the N-3 position may generate a stronger interaction with their target sites, as predicted by the type 2 pharmacophore model.…”

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confidence: 99%

Mechanism and Site of Inhibition of AMPA Receptors: Pairing a Thiadiazole with a 2,3-Benzodiazepine Scaffold

Wang

Yao

et al. 2013

ACS Chem. Neurosci.

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2,3-Benzodiazepine compounds are synthesized as drug candidates for treatment of various neurological disorders involving excessive activity of AMPA receptors. Here we report that pairing a thiadiazole moiety with a 2,3-benzodiazepine scaffold via the N-3 position yields an inhibitor type with >28-fold better potency and selectivity on AMPA receptors than the 2,3-benzodiazepine scaffold alone. Using wholecell recording, we characterized two thiadiazolyl compounds, that is, one contains a 1,3,4-thiadiazole moiety and the other contains a 1,2,4-thiadiazole-3-one moiety. These compounds exhibit potent, equal inhibition of both the closed-channel and the open-channel conformations of all four homomeric AMPA receptor channels and two GluA2R-containing complex AMPA receptor channels. Furthermore, these compounds bind to the same receptor site as GYKI 52466 does, a site we previously termed as the "M" site. A thiadiazole moiety is thought to occupy more fully the side pocket of the receptor site or the "M" site, thereby generating a stronger, multivalent interaction between the inhibitor and the receptor binding site. We suggest that, as a heterocycle, a thiadiazole can be further modified chemically to produce a new class of even more potent, noncompetitive inhibitors of AMPA receptors.

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New non competitive AMPA antagonists

Cited by 53 publications

References 43 publications

Heterogeneity and potentiation of AMPA type of glutamate receptors in rat cultured microglia

Heterogeneity and potentiation of AMPA type of glutamate receptors in rat cultured microglia

Inhibition of Calcineurin-mediated Endocytosis and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Prevents Amyloid β Oligomer-induced Synaptic Disruption

Mechanism and Site of Inhibition of AMPA Receptors: Pairing a Thiadiazole with a 2,3-Benzodiazepine Scaffold

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