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

Result code in 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>
Alternative codes found
RIV/67985823:_____/18:00490287 RIV/61388963:_____/18:00490287 RIV/00216208:11120/18:43916667
Result on the web
<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>

Result language
angličtina
Original language name
Positive Modulators of the N-Methyl-D-aspartate Receptor: Structure-Activity Relationship Study of Steroidal 3-Hemiesters
Original language description
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.
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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