title: Neurosteroid-like Inhibitors of N-Methyl-d-aspartate Receptor: Substituted 2-Sulfates and 2-Hemisuccinates of Perhydrophenanthrene.
abstract: N-Methyl-d-aspartate receptors (NMDARs) display a critical role in various diseases of the central nervous system. The activity of NMDARs can be modulated by neurosteroids. Herein, we report a structure-activity relationship study for perhydrophenanthrene analogues possessing a framework that mimics the steroidal ring system. This study comprises the design, synthesis, and assessment of the biological activity of a library of perhydrophenanthrene 2-sulfates and 2-hemisuccinates (1-10). Their ability to modulate NMDAR-induced currents was tested on recombinant GluN1/GluN2B receptors. Our results demonstrate that such structural optimization leads to compounds that are inhibitors of NMDARs. Notably, compound 9 (IC50 = 15.6 μM) was assessed as a more potent inhibitor of NMDAR-induced currents than the known endogenous 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, Dejvice, Prague 6, 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, Dejvice, Prague 6, 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, Dejvice, Prague 6, 16610, Czech Republic.|Faculty of Mathematics and Physics, Charles University in Prague , Ke Karlovu 3, Prague 2, 121 16, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nekardova
authors.affiliation: Institute of Physiology CAS , Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Vojtech
authors.initials: V
authors.lastname: Vyklicky
authors.affiliation: Institute of Physiology CAS , Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Ladislav
authors.affiliation: Institute of Physiology CAS , Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Hubalkova
authors.affiliation: Institute of Physiology CAS , Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Krausova
authors.affiliation: Institute of Physiology CAS , Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Vyklicky
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Dejvice, Prague 6, 16610, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Kudova
mesh_terms: D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013386:Succinates / Q000737:chemistry / Q000494:pharmacology*; D013431:Sulfates / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D010616:Phenanthrenes; D016194:Receptors, N-Methyl-D-Aspartate; D013386:Succinates; D013431:Sulfates