Positive Modulators of the N-Methyl-D-aspartate Receptor: Structure-Activity Relationship Study of Steroidal 3-Hemiesters

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11320%2F18%3A10375959" target="_blank" >RIV/00216208:11320/18:10375959 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/67985823:_____/18:00490287 RIV/61388963:_____/18:00490287 RIV/00216208:11120/18:43916667

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00255" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00255</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.8b00255" target="_blank" >10.1021/acs.jmedchem.8b00255</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Positive Modulators of the N-Methyl-D-aspartate Receptor: Structure-Activity Relationship Study of Steroidal 3-Hemiesters

Popis výsledku v původním jazyce

Here, we report the synthesis of pregn-5-ene and androst-5-ene dicarboxylic acid esters and explore the structure activity relationship (SAR) for their modulation of N-methyl-D-aspartate receptors (NMDARs). All compounds were positive modulators of recombinant GluN1/GluN2B receptors (EC50 varying from 1.8 to 151.4 mu M and E-max, varying from 48% to 452%). Moreover, 10 compounds were found to be more potent GluN1/GluN2B receptor modulators than endogenous pregnenolone sulfate (EC50 = 21.7 mu M). The SAR study revealed a relationship between the length of the residues at carbon C-3 of the steroid molecule and the positive modulatory effect at GluN1/GluN2B receptors for various D-ring modifications. A selected compound, 20-oxo-pregnenolone hemiadipate, potentiated native NMDARs to a similar extent as GluN1/GluN2A-D receptors and inhibited AMPARs and GABA(A)R responses. These results provide a unique opportunity for the development of new steroid based drugs with potential use in the treatment of neuropsychiatric disorders involving hypofunction of NMDARs.

Název v anglickém jazyce

Positive Modulators of the N-Methyl-D-aspartate Receptor: Structure-Activity Relationship Study of Steroidal 3-Hemiesters

Popis výsledku anglicky

Here, we report the synthesis of pregn-5-ene and androst-5-ene dicarboxylic acid esters and explore the structure activity relationship (SAR) for their modulation of N-methyl-D-aspartate receptors (NMDARs). All compounds were positive modulators of recombinant GluN1/GluN2B receptors (EC50 varying from 1.8 to 151.4 mu M and E-max, varying from 48% to 452%). Moreover, 10 compounds were found to be more potent GluN1/GluN2B receptor modulators than endogenous pregnenolone sulfate (EC50 = 21.7 mu M). The SAR study revealed a relationship between the length of the residues at carbon C-3 of the steroid molecule and the positive modulatory effect at GluN1/GluN2B receptors for various D-ring modifications. A selected compound, 20-oxo-pregnenolone hemiadipate, potentiated native NMDARs to a similar extent as GluN1/GluN2A-D receptors and inhibited AMPARs and GABA(A)R responses. These results provide a unique opportunity for the development of new steroid based drugs with potential use in the treatment of neuropsychiatric disorders involving hypofunction of NMDARs.

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

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

—

Svazek periodika

61

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

4505-4516

Kód UT WoS článku

000433403600016

EID výsledku v databázi Scopus

2-s2.0-85046664936