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

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• 作者：Eva Kudova ; Hana Chodounska ; Barbora Slavikova ; Milos Budesinsky ; Michaela Nekardova ; Vojtech Vyklicky ; Barbora Krausova ; Pavel Svehla ; Ladislav Vyklicky
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：58
• 期：15
• 页码：5950-5966
• 全文大小：624K
• ISSN：1520-4804

文摘

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鈥揳ctivity 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 渭M) than the known endogeneous neurosteroid鈥損regnanolone sulfate (IC₅₀ = 24.6 渭M).