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Research ArticleArticle

Effects of the Potent Ampakine CX614 on Hippocampal and Recombinant AMPA Receptors: Interactions with Cyclothiazide and GYKI 52466

Amy C. Arai, Markus Kessler, Gary Rogers and Gary Lynch
Molecular Pharmacology October 2000, 58 (4) 802-813; DOI: https://doi.org/10.1124/mol.58.4.802
Amy C. Arai
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Markus Kessler
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Gary Rogers
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Abstract

R,S-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor up-modulators of the benzamide type (“ampakines”) have previously been shown to enhance excitatory synaptic transmission in vivo and in vitro and AMPA receptor currents in excised patches. The present study analyzed the effects of an ampakine (CX614; 2H,3H,6aH-pyrrolidino[2",1"-3′,2′]1,3-oxazino[6′,5′-5,4]benzo[e]1,4-dioxan-10-one) that belongs to a benzoxazine subgroup characterized by greater structural rigidity and higher potency. CX614 enhanced the size (amplitude and duration) of field excitatory postsynaptic potentials in hippocampal slices and autaptically evoked excitatory postsynaptic currents in neuronal cultures with EC50 values of 20 to 40 μM. The compound blocked desensitization (EC50 = 44 μM) and slowed deactivation of responses to glutamate by a factor of 8.4 in excised patches. Currents through homomeric, recombinant AMPA receptors were enhanced with EC50 values that did not differ greatly across GluR1–3 flop subunits (19–37 μM) but revealed slightly lower potency at corresponding flip variants. Competition experiments using modulation of [3H]fluorowillardiine binding suggested that CX614 and cyclothiazide share a common binding site but cyclothiazide seems to bind to an additional site not recognized by the ampakine. CX614 did not reverse the effect of GYKI 52466 on responses to brief glutamate pulses, which indicates that they act through separate sites, a conclusion that was confirmed in binding experiments. In sum, these results extend prior evidence that ampakines are effective in enhancing synaptic responses, most likely by slowing deactivation, and that their effects are exerted through sites that are only in part shared with other modulators.

Footnotes

    • Received February 22, 2000.
    • Accepted June 23, 2000.
  • Send reprint requests to: Dr. A. Arai, Southern Illinois University, School of Medicine, Dept. of Pharmacology, 801 N. Rutledge, Springfield, IL 62794-9629. E-mail:aarai{at}siumed.edu

  • This work was supported by grants from Cortex Pharmaceuticals (CP19982), the National Science Foundation (IBN-9806215), and the Air Force Office of Scientific Research (F49620-95-1-0304).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 58 (4)
Molecular Pharmacology
Vol. 58, Issue 4
1 Oct 2000
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Research ArticleArticle

Effects of the Potent Ampakine CX614 on Hippocampal and Recombinant AMPA Receptors: Interactions with Cyclothiazide and GYKI 52466

Amy C. Arai, Markus Kessler, Gary Rogers and Gary Lynch
Molecular Pharmacology October 1, 2000, 58 (4) 802-813; DOI: https://doi.org/10.1124/mol.58.4.802

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Research ArticleArticle

Effects of the Potent Ampakine CX614 on Hippocampal and Recombinant AMPA Receptors: Interactions with Cyclothiazide and GYKI 52466

Amy C. Arai, Markus Kessler, Gary Rogers and Gary Lynch
Molecular Pharmacology October 1, 2000, 58 (4) 802-813; DOI: https://doi.org/10.1124/mol.58.4.802
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