A New Class of Potent N-Methyl-D-Aspartate Receptor Inhibitors: Sulfated Neuroactive Steroids with Lipophilic D-Ring Modifications

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11320%2F15%3A10392664" target="_blank" >RIV/00216208:11320/15:10392664 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/67985823:_____/15:00447623 RIV/61388963:_____/15:00447623

Výsledek na webu

<a href="https://doi.org/10.1021/acs.jmedchem.5b00570" target="_blank" >https://doi.org/10.1021/acs.jmedchem.5b00570</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.5b00570" target="_blank" >10.1021/acs.jmedchem.5b00570</a>

Jazyk výsledku

angličtina

Název v původním jazyce

A New Class of Potent N-Methyl-D-Aspartate Receptor Inhibitors: Sulfated Neuroactive Steroids with Lipophilic D-Ring Modifications

Popis výsledku v původním jazyce

N-Methyl-u-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 1)-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 mu M) than the known endogeneous neurosteroid pregnanolone sulfate (IC50 = 24.6 mu M).

Název v anglickém jazyce

A New Class of Potent N-Methyl-D-Aspartate Receptor Inhibitors: Sulfated Neuroactive Steroids with Lipophilic D-Ring Modifications

Popis výsledku anglicky

N-Methyl-u-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 1)-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 mu M) than the known endogeneous neurosteroid pregnanolone sulfate (IC50 = 24.6 mu M).

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

<a href="/cs/project/ED1.1.00%2F02.0109" target="_blank" >ED1.1.00/02.0109: Biotechnologické a biomedicínské centrum Akademie věd a Univerzity Karlovy</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2015

Kód důvěrnosti údajů

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

Název periodika

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

—

Svazek periodika

58

Číslo periodika v rámci svazku

15

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

17

Strana od-do

5950-5966

Kód UT WoS článku

000359683700019

EID výsledku v databázi Scopus

2-s2.0-84939159901