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Tytuł:
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Electrophysiological characterization of a novel AMPA receptor potentiator, TAK-137, in rat hippocampal neurons.
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Autorzy:
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Suzuki A; Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan. Electronic address: .
Tajima Y; Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan. Electronic address: .
Kunugi A; Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan. Electronic address: .
Kimura H; Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan. Electronic address: .
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Źródło:
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Neuroscience letters [Neurosci Lett] 2019 Nov 01; Vol. 712, pp. 134488. Date of Electronic Publication: 2019 Sep 10.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Limerick : Elsevier Scientific Publishers Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.
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MeSH Terms:
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Evoked Potentials/*drug effects
Excitatory Amino Acid Agonists/*pharmacology
Hippocampus/*drug effects
Neurons/*drug effects
Pyridines/*pharmacology
Receptors, AMPA/*metabolism
Thiadiazines/*pharmacology
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/*pharmacology
Animals ; Benzodiazepines/pharmacology ; Excitatory Amino Acid Antagonists/pharmacology ; Hippocampus/metabolism ; Male ; Neurons/metabolism ; Patch-Clamp Techniques ; Rats ; Rats, Sprague-Dawley
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Contributed Indexing:
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Keywords: AMPA receptor potentiator; Agonistic effect; LY451646; TAK-137
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Substance Nomenclature:
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0 (Excitatory Amino Acid Agonists)
0 (Excitatory Amino Acid Antagonists)
0 (Pyridines)
0 (Receptors, AMPA)
0 (Thiadiazines)
12794-10-4 (Benzodiazepines)
146908-67-0 (GYKI 53655)
77521-29-0 (alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid)
XE1054JW00 (TAK-137)
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Entry Date(s):
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Date Created: 20190914 Date Completed: 20200923 Latest Revision: 20200923
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Update Code:
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20240105
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DOI:
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10.1016/j.neulet.2019.134488
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PMID:
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31518676
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We have recently discovered an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) potentiator TAK-137, 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4] thiadiazine 2,2-dioxide with little agonistic effect. Under preclinical evaluation, TAK-137 demonstrated potent pro-cognitive effects with lower risks of seizure and bell-shaped dose response than LY451646, a potent AMPA-R potentiator, in rodents and monkeys. In this study, using rat primary cultured hippocampal neurons we explored the electrophysiological characterization of TAK-137 on native AMPA-Rs. TAK-137 dose-dependently enhanced AMPA-induced inward currents; its potency in the presence of AMPA was comparable to that of LY451646. The inward currents enhanced by TAK-137 were almost completely inhibited by GYKI53655, a selective AMPA-R blocker. Moreover, TAK-137 did not affect N-methyl- D -aspartate (NMDA)-activated inward currents, which suggests the AMPA-R-selective activation by TAK-137. In the absence of AMPA-R agonist, LY451646 at 30 μM induced slowly developing large inward currents, whereas TAK-137 at 30 μM exhibited a slight impact on baseline holding currents, further supporting the lower agonistic properties of TAK-137 than LY451646. Similar to LY451646, TAK-137 also increased the potency and binding affinity of AMPA for AMPA-Rs. These results indicate that TAK-137 is a highly potent and selective potentiator with little agonistic effect against native AMPA-Rs. Much greater agonistic effects of LY451646 than of TAK-137 may contribute to the increased risks of seizure and bell-shaped dose response in vivo.
(Copyright © 2019 Elsevier B.V. All rights reserved.)