0490287 - FGÚ 2019 RIV US eng J - Journal Article
Krausová, Barbora - Slavíková, Barbora - Nekardová, Michaela - Hubálková, Pavla - Vyklický, Vojtěch - Chodounská, Hana - Vyklický ml., Ladislav - Kudová, Eva
Positive Modulators of the N-Methyl-D-aspartate Receptor: Structure-Activity Relationship Study of Steroidal 3-Hemiesters.
Journal of Medicinal Chemistry. Roč. 61, č. 10 (2018), s. 4505-4516. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR(CZ) GA17-02300S; GA ČR(CZ) GBP208/12/G016; GA TA ČR(CZ) TE01020028; GA MZd(CZ) NV15-29370A; GA MŠMT(CZ) ED1.1.00/02.0109
Grant - others:AV ČR(CZ) MSM200111601
Program: Program na podporu mezinárodní spolupráce začínajících výzkumných pracovníků
Institutional support: RVO:67985823 ; RVO:61388963
Keywords : neurosteroids * N-Methyl-D-aspartate receptor * positive modulators
OECD category: Neurosciences (including psychophysiology
Impact factor: 6.054, year: 2018

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.
Permanent Link: http://hdl.handle.net/11104/0284547