A New Class of Potent <i>N</i>‑Methyl‑d‑Aspartate Receptor Inhibitors: Sulfated Neuroactive Steroids with Lipophilic D‑Ring Modifications

Abstract

<i>N</i>-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)