Strong Inhibitory Effect, Low Cytotoxicity and High Plasma Stability of Steroidal Inhibitors of N-Methyl-D-Aspartate Receptors With C-3 Amide Structural Motif

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00498559" target="_blank" >RIV/61388963:_____/18:00498559 - isvavai.cz</a>
Alternative codes found
RIV/67985823:_____/18:00498559 RIV/00216208:11320/18:10439840
Result on the web
<a href="https://www.frontiersin.org/articles/10.3389/fphar.2018.01299/full" target="_blank" >https://www.frontiersin.org/articles/10.3389/fphar.2018.01299/full</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.3389/fphar.2018.01299" target="_blank" >10.3389/fphar.2018.01299</a>

Result language
angličtina
Original language name
Strong Inhibitory Effect, Low Cytotoxicity and High Plasma Stability of Steroidal Inhibitors of N-Methyl-D-Aspartate Receptors With C-3 Amide Structural Motif
Original language description
Herein, we report the synthesis, structure-activity relationship study, and biological evaluation of neurosteroid inhibitors of N-methyl-D-aspartate receptors (NMDARs) receptors that employ an amide structural motif, relative to pregnanolone glutamate (PAG) a compound with neuroprotective properties. All compounds were found to be more potent NMDAR inhibitors (IC50 values varying from 1.4 to 21.7 mu M) than PAG (IC50 = 51.7 mu M). Selected compound 6 was evaluated for its NMDAR subtype selectivity and its ability to inhibit AMPAR/GABAR responses. Compound 6 inhibits the NMDARs (8.3 receptors (8.3 +/- 2.1 mu M) more strongly than it does at the GABAR and AMPARs (17.0 receptors (17.0 +/- 0.2 mu M and 276.4 +/- 178.7 mu M, respectively). In addition, compound 6 (10 mu M) decreases the frequency of action potentials recorded in cultured hippocampal neurons. Next, compounds 3, 5-7, 9, and 10 were not associated with mitotoxicity, hepatotoxicity nor ROS induction. Lastly, we were able to show that all compounds have improved rat and human plasma stability over PAG.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology

Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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