title: Physicochemical and biological properties of novel amide-based steroidal inhibitors of NMDA receptors.
abstract: Herein, we report a new class of amide-based inhibitors (1-4) of N-methyl-d-aspartate receptors (NMDARs) that were prepared as analogues of pregnanolone sulfate (PAS) and pregnanolone glutamate (PAG) - the steroidal neuroprotective NMDAR inhibitors. A series of experiments were conducted to evaluate their physicochemical and biological properties: (i) the inhibitory effect of compounds 3 and 4 on NMDARs was significantly improved (IC50=1.0 and 1.4μM, respectively) as compared with endogenous inhibitor - pregnanolone sulfate (IC50=24.6μM) and pregnanolone glutamate (IC50=51.7μM); (ii) physicochemical properties (logP and logD) were calculated; (iii) Caco-2 assay revealed that the permeability properties of compounds 2 and 4 are comparable with pregnanolone glutamate; (iv) compounds 1-4 have minimal or no adverse hepatic effect; (v) compounds 1-4 cross blood-brain-barrier.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Prague 6 - Dejvice, 166 10, Czech Republic.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Adla
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Prague 6 - Dejvice, 166 10, 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, 166 10, Czech Republic.
authors.forename: Marketa
authors.initials: M
authors.lastname: Smidkova
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Prague 6 - Dejvice, 166 10, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Tloustova
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Prague 6 - Dejvice, 166 10, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Svoboda
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Vojtech
authors.initials: V
authors.lastname: Vyklicky
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Krausova
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic; Charles University in Prague, Third Faculty of Medicine, Ruska 87, Prague 10, 100 00, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Hubalkova
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Prague 6 - Dejvice, 166 10, 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 of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Kristina
authors.initials: K
authors.lastname: Holubova
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Vales
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Prague 6 - Dejvice, 166 10, Czech Republic.
authors.forename: Milos
authors.initials: M
authors.lastname: Budesinsky
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, 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, Prague 6 - Dejvice, 166 10, 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, 166 10, Czech Republic. Electronic address: kudova@uochb.cas.cz.
authors.forename: Eva
authors.initials: E
authors.lastname: Kudova
mesh_terms: D000577:Amides; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D018938:Caco-2 Cells; D056945:Hep G2 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D018377:Neurotransmitter Agents / Q000737:chemistry* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D018377:Neurotransmitter Agents; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Amide; Blood-brain-barrier permeability; Caco-2 assay; NMDA receptor; Neurosteroid; Structure-activity relationship