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P4–430: New group of positive modulators of AMPA–receptors
Author(s) -
Grigoriev Vladimir
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.2172
Subject(s) - ampa receptor , receptor , kainate receptor , chemistry , kainic acid , neuroscience , desensitization (medicine) , glutamate receptor , pharmacology , long term depression , biophysics , biology , biochemistry
According to the results of 3D-docking of model positive modulators of AMPA receptors on “ampakine’s” binding site of this receptor a radically new group of compounds, which could be characterized as “dimeric ampakines” was designed. We have studied the action of these compounds on AMPA receptors and their behavioral effect in the test of object recognition. In particular, their effect on transmembrane currents evoked application of kainic acid (KA) on neurons from rat brain was studied by patch-clamp method. It was revealed that compounds demonstrate dose-dependent potentiating effect on currents induced by KA acid on Purkinje cells. Comparative investigation of potentiating effect of hit-compound of this group LM-01 and Cyclothiazide permitted to suggest that LM-01 might block desensitization processes induced by AMPA receptors agonists. It was shown that it increased KA-induced currents in so small doses as 0.11.0 pM. In higher doses (about 10-100 nM) its potentiating effect disappeared that pointed on bell-shaped dose-dependence. It was revealed that LM-01 and some of its analogues enhanced memory and cognition in male mice C57/Bl6 in the object recognition test in doses less than 0.01 mg/kg. It was suggested that new “dimeric ampakines” represent new group of positive modulators of AMPA receptors, which was able to block desensitization of AMPA receptors and to enhance of cognition in experimental animals in object recognition test in very small doses.