AUTHOR=Adla Santosh Kumar , Slavikova Barbora , Chodounska Hana , Vyklicky Vojtech , Ladislav Marek , Hubalkova Pavla , Krausova Barbora , Smejkalova Tereza , Nekardova Michaela , Smidkova Marketa , Monincova Lenka , Soucek Radko , Vyklicky Ladislav , Kudova Eva 

TITLE=Strong Inhibitory Effect, Low Cytotoxicity and High Plasma Stability of Steroidal Inhibitors of N-Methyl-D-Aspartate Receptors With C-3 Amide Structural Motif

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.01299

DOI=10.3389/fphar.2018.01299

ISSN=1663-9812

ABSTRACT=<p>Herein, we report the synthesis, structure-activity relationship study, and biological evaluation of neurosteroid inhibitors of <italic>N</italic>-methyl-<sc>D</sc>-aspartate receptors (NMDARs) receptors that employ an amide structural motif, relative to pregnanolone glutamate (PAG) – a compound with neuroprotective properties. All compounds were found to be more potent NMDAR inhibitors (IC<sub>50</sub> values varying from 1.4 to 21.7 μM) than PAG (IC<sub>50</sub> = 51.7 μM). Selected compound 6 was evaluated for its NMDAR subtype selectivity and its ability to inhibit AMPAR/GABAR responses. Compound 6 inhibits the NMDARs (8.3 receptors (8.3 ± 2.1 μM) more strongly than it does at the GABAR and AMPARs (17.0 receptors (17.0 ± 0.2 μM and 276.4 ± 178.7 μM, respectively). In addition, compound 6 (10 μM) decreases the frequency of action potentials recorded in cultured hippocampal neurons. Next, compounds 3, 5–7, 9, and 10 were not associated with mitotoxicity, hepatotoxicity nor ROS induction. Lastly, we were able to show that all compounds have improved rat and human plasma stability over PAG.</p>