Novel Potent Orthosteric Antagonist of ASIC1a Prevents NMDAR-Dependent LTP Induction. J Med Chem 2015 Jun 11;58(11):4449-61
Date
05/15/2015Pubmed ID
25974655DOI
10.1021/jm5017329Scopus ID
2-s2.0-84935857385 (requires institutional sign-in at Scopus site) 31 CitationsAbstract
Acid sensing ion channels 1a (ASIC1a) are of crucial importance in numerous physiological and pathological processes in the brain. Here we demonstrate that novel 2-oxo-2H-chromene-3-carboxamidine derivative 5b, designed with molecular modeling approach, inhibits ASIC1a currents with an apparent IC50 of 27 nM when measured at pH 6.7. Acidification to 5.0 decreases the inhibition efficacy by up to 3 orders of magnitude. The 5b molecule not only shifts pH dependence of ASIC1a activation but also inhibits its maximal evoked response. These findings suggest that compound 5b binds to pH sensor of ASIC1a acting as orthosteric noncompetitive antagonist. At 100 nM, compound 5b completely inhibits induction of long-term potentiation (LTP) in CA3-CA1 but not in MF-CA3 synapses. These findings support the knockout data indicating the crucial modulatory role of ASIC1a channels in the NMDAR-dependent LTP and introduce a novel type of ASIC1a antagonists.
Author List
Buta A, Maximyuk O, Kovalskyy D, Sukach V, Vovk M, Ievglevskyi O, Isaeva E, Isaev D, Savotchenko A, Krishtal OAuthor
Olena Isaeva PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Acid Sensing Ion ChannelsAmidines
Animals
Cells, Cultured
Coumarins
HEK293 Cells
Hippocampus
Humans
Long-Term Potentiation
Models, Molecular
Molecular Structure
Neurons
Patch-Clamp Techniques
Rats
Rats, Wistar
Receptors, N-Methyl-D-Aspartate
Structure-Activity Relationship
Synapses
