title: 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).
authors.affiliation: †Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nam 2, Prague 6-Dejvice, 16610, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Kudova
authors.affiliation: †Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nam 2, Prague 6-Dejvice, 16610, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Chodounska
authors.affiliation: †Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nam 2, Prague 6-Dejvice, 16610, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Slavikova
authors.affiliation: †Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nam 2, Prague 6-Dejvice, 16610, Czech Republic.
authors.forename: Milos
authors.initials: M
authors.lastname: Budesinsky
authors.affiliation: †Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nam 2, Prague 6-Dejvice, 16610, Czech Republic.|§Faculty of Mathematics and Physics, Charles University in Prague, Ke Karlovu 3, Prague 2, 12116, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nekardova
authors.affiliation: ‡Institute of Physiology, Academy of Sciences of the Czech Republic v.v.i., Videnska 1083, Prague 4, 14220, Czech Republic.
authors.forename: Vojtech
authors.initials: V
authors.lastname: Vyklicky
authors.affiliation: ‡Institute of Physiology, Academy of Sciences of the Czech Republic v.v.i., Videnska 1083, Prague 4, 14220, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Krausova
authors.affiliation: ‡Institute of Physiology, Academy of Sciences of the Czech Republic v.v.i., Videnska 1083, Prague 4, 14220, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Svehla
authors.affiliation: ‡Institute of Physiology, Academy of Sciences of the Czech Republic v.v.i., Videnska 1083, Prague 4, 14220, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Vyklicky
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology*; D013431:Sulfates / Q000737:chemistry
chemical_list: D008055:Lipids; D016194:Receptors, N-Methyl-D-Aspartate; D013256:Steroids; D013431:Sulfates