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J Med Chem. 2015 Jun 11;58(11):4449-61. doi: 10.1021/jm5017329. Epub 2015 May 29.

Novel Potent Orthosteric Antagonist of ASIC1a Prevents NMDAR-Dependent LTP Induction.

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†Bogomoletz Institute of Physiology of NAS Ukraine, 4 Bogomoletz Str., 01024 Kyiv, Ukraine.
§State Key Laboratory for Molecular and Cellular Biology, 4 Bogomoletz Str., 01024 Kyiv, Ukraine.
∥ChemBio Center, Taras Shevchenko University of Kyiv, 67 Chervonotkatska Str., 02094 Kyiv, Ukraine.
‡Institute of Organic Chemistry of NAS Ukraine, 5 Murmanska Str., 02660 Kyiv, Ukraine.


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.

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