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

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/67985823:_____/18:00498559 RIV/00216208:11320/18:10439840

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Frontiers in Pharmacology

ISSN

1663-9812

e-ISSN

—

Svazek periodika

9

Číslo periodika v rámci svazku

Nov 12

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

16

Strana od-do

—

Kód UT WoS článku

000449859800001

EID výsledku v databázi Scopus

2-s2.0-85056740159