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

Abstract

N-Methyl-D-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 D-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 μM) than the known endogeneous neurosteroid-pregnanolone sulfate (IC50 = 24.6 μM).

DOI: 10.1021/acs.jmedchem.5b00570

Cite this paper

@article{Kudov2015ANC, title={A New Class of Potent N-Methyl-D-Aspartate Receptor Inhibitors: Sulfated Neuroactive Steroids with Lipophilic D-Ring Modifications.}, author={Eva Kudov{\'a} and Hana Chodounsk{\'a} and Barbora Slav{\'i}kov{\'a} and Milo{\vs} Budě{\vs}{\'i}nsk{\'y} and Michaela Nekardov{\'a} and Vojtech Vyklicky and Barbora Krausov{\'a} and Pavel {\vS}vehla and Ladislav Vyklick{\'y}}, journal={Journal of medicinal chemistry}, year={2015}, volume={58 15}, pages={5950-66} }