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A New Class of Potent N-Methyl-D-Aspartate Receptor Inhibitors: Sulfated Neuroactive Steroids with Lipophilic D-Ring Modifications
E. Kudova, H. Chodounska, B. Slavikova, M. Budesinsky, M. Nekardova, V. Vyklicky, B. Krausova, P. Svehla, L. Vyklicky,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- HEK293 Cells MeSH
- Humans MeSH
- Lipids chemistry MeSH
- Receptors, N-Methyl-D-Aspartate antagonists & inhibitors MeSH
- Sulfates chemistry MeSH
- Steroids chemistry pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play a crucial role in excitatory synaptic transmission. However, the overactivation of NMDARs can lead to excitotoxic cell damage/death, and as such, they play a role in numerous neuropathological conditions. The activity of NMDARs is known to be influenced by a wide variety of allosteric modulators, including neurosteroids, which in turn makes them promising therapeutic targets. In this study, we describe a new class of neurosteroid analogues which possess structural modifications in the steroid D-ring region. These analogues were tested on recombinant GluN1/GluN2B receptors to evaluate the structure-activity relationship. Our results demonstrate that there is a strong correlation between this new structural feature and the in vitro activity, as all tested compounds were evaluated as more potent inhibitors of NMDA-induced currents (IC50 values varying from 90 nM to 5.4 μM) than the known endogeneous neurosteroid-pregnanolone sulfate (IC50 = 24.6 μM).
References provided by Crossref.org
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- $a Kudova, Eva $u †Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nam 2, Prague 6-Dejvice, 16610, Czech Republic.
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- $a N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play a crucial role in excitatory synaptic transmission. However, the overactivation of NMDARs can lead to excitotoxic cell damage/death, and as such, they play a role in numerous neuropathological conditions. The activity of NMDARs is known to be influenced by a wide variety of allosteric modulators, including neurosteroids, which in turn makes them promising therapeutic targets. In this study, we describe a new class of neurosteroid analogues which possess structural modifications in the steroid D-ring region. These analogues were tested on recombinant GluN1/GluN2B receptors to evaluate the structure-activity relationship. Our results demonstrate that there is a strong correlation between this new structural feature and the in vitro activity, as all tested compounds were evaluated as more potent inhibitors of NMDA-induced currents (IC50 values varying from 90 nM to 5.4 μM) than the known endogeneous neurosteroid-pregnanolone sulfate (IC50 = 24.6 μM).
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- $a Nekardova, Michaela $u †Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nam 2, Prague 6-Dejvice, 16610, Czech Republic. §Faculty of Mathematics and Physics, Charles University in Prague, Ke Karlovu 3, Prague 2, 12116, Czech Republic.
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