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Vol. 58, Issue 4, 802-813, October 2000
Department of Pharmacology, Southern Illinois University,
Springfield, Illinois (A.C.A., M.K.); Department of Psychiatry,
University of California, Irvine, California (G.L.); and Cortex
Pharmaceuticals Inc., Irvine, California (G.R.)
R,S-
-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.
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