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

被引：35

作者：

Buta, Andriy ^{[1
,3
]}

Maximyuk, Oleksandr ^{[1
,3
]}

Kovalskyy, Dmytro ^{[4
]}

Sukach, Volodymyr ^{[2
]}

Vovk, Mykhailo ^{[2
]}

Ievglevskyi, Oleksandr ^{[1
]}

Isaeva, Elena ^{[1
]}

Isaev, Dmytro ^{[1
]}

Savotchenko, Alina ^{[1
]}

Krishtal, Oleg ^{[1
,3
]}

机构：

[1] Bogomoletz Inst Physiol NAS Ukraine, UA-01024 Kiev, Ukraine

[2] Inst Organ Chem NAS Ukraine, UA-02660 Kiev, Ukraine

[3] State Key Lab Mol & Cellular Biol, UA-01024 Kiev, Ukraine

[4] Taras Shevchenko Univ Kyiv, ChemBio Ctr, UA-02094 Kiev, Ukraine

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 11期

关键词：

SENSING ION CHANNELS; TARANTULA TOXIN PSALMOTOXIN-1; LONG-TERM POTENTIATION; SENSORY NEURONS; SYNAPTIC PLASTICITY; THERAPEUTIC TARGETS; AMILORIDE BLOCK; INHIBITORS; RECEPTOR; PROTONS;

D O I：

10.1021/jm5017329

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Acid sensing ion channels la (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.

引用

页码：4449 / 4461

页数：13