Positive Modulators of the N-Methyl-d-aspartate Receptor: Structure-Activity Relationship Study of Steroidal 3-Hemiesters
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Allosteric Regulation MeSH
- HEK293 Cells MeSH
- Protein Conformation MeSH
- Humans MeSH
- Membrane Transport Modulators chemistry pharmacology MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Pregnenolone pharmacology MeSH
- Receptors, N-Methyl-D-Aspartate antagonists & inhibitors metabolism MeSH
- Steroids chemistry pharmacology MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Membrane Transport Modulators MeSH
- Pregnenolone MeSH
- pregnenolone sulfate MeSH Browser
- Receptors, N-Methyl-D-Aspartate MeSH
- Steroids MeSH
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 μM and Emax 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 μM). 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 GABAAR 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.
References provided by Crossref.org
C-3 Steroidal Hemiesters as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 10
Site of Action of Brain Neurosteroid Pregnenolone Sulfate at the N-Methyl-D-Aspartate Receptor
