AUTHOR=Bukanova Julia V. , Solntseva Elena I. , Kudova Eva 

TITLE=Neurosteroids as Selective Inhibitors of Glycine Receptor Activity: Structure-Activity Relationship Study on Endogenous Androstanes and Androstenes

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=13

YEAR=2020

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2020.00044

DOI=10.3389/fnmol.2020.00044

ISSN=1662-5099

ABSTRACT=<p>The ability of androstane and androstene neurosteroids with modifications at C-17, C-5, and C-3 (compounds <bold>1</bold>-<bold>9</bold>) to influence the functional activity of inhibitory glycine and γ-aminobutyric acid (GABA) receptors was estimated. The glycine- and GABA-induced chloride current (<italic>I</italic><sub>Gly</sub> and <italic>I</italic><sub>GABA</sub>) were measured in isolated pyramidal neurons of the rat hippocampus and isolated rat cerebellar Purkinje cells, correspondingly, using the patch-clamp technique. Our results demonstrate that all the nine neurosteroids display similar biological activity, namely, they strongly inhibited <italic>I</italic><sub>Gly</sub> and weakly inhibited <italic>I</italic><sub>GABA</sub>. The threshold concentration of neurosteroids inducing effects on <italic>I</italic><sub>Gly</sub> was 0.1 μM, and for effects on <italic>I</italic><sub>GABA</sub> was 10–50 μM. Moreover, our compounds accelerated desensitization of the <italic>I</italic><sub>Gly</sub> with the IC<sub>50</sub> values varying from 0.12 to 0.49 μM and decreased the peak amplitude with IC<sub>50</sub> values varying from 16 to 22 μM. Interestingly, our study revealed that only compounds <bold>4</bold> (epiandrosterone) and <bold>8</bold> (dehydroepiandrosterone) were able to cause a significant change in <italic>I</italic><sub>GABA</sub> in 10 μM concentration. Moreover, compounds <bold>3</bold> (testosterone), <bold>5</bold> (epitestosterone), <bold>6</bold> (dihydroandrostenedione), and <bold>9</bold> (etiocholanedione) did not modulate <italic>I</italic><sub>GABA</sub> up to the concentration of 50 μM. Thus, we conclude that compounds <bold>3</bold>, <bold>5</bold>, <bold>6</bold>, and <bold>9</bold> may be identified as selective modulators of <italic>I</italic><sub>Gly</sub>. Our results offer new avenues of investigation in the field of drug-like selective modulators of <italic>I</italic><sub>Gly</sub>.</p>