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

• Published in: Frontiers in molecular neuroscience Vol. 13; p. 44
• Main Authors: Bukanova, Julia V, Solntseva, Elena I, Kudova, Eva
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 20-03-2020; Frontiers Media S.A
• Subjects: androstane; androstene; Autism; Biological activity; Cerebellum; Chloride currents; Cholesterol; Dehydroepiandrosterone; GABA receptor; glycine receptor; Ligands; Mutation; Nervous system; Neurological disorders; Neuromodulation; Neuroscience; neurosteroid; Neurosteroids; Pain; Purkinje cells; Pyramidal cells; Steroids; structure-activity relationship; Testosterone; γ-Aminobutyric acid; GABA receptor; glycine receptor; androstene; structure-activity relationship; neurosteroid; androstane
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2020.00044

The ability of androstane and androstene neurosteroids with modifications at C-17, C-5, and C-3 (compounds
-
) to influence the functional activity of inhibitory glycine and γ-aminobutyric acid (GABA) receptors was estimated. The glycine- and GABA-induced chloride current (
and
) 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
and weakly inhibited
. The threshold concentration of neurosteroids inducing effects on
was 0.1 μM, and for effects on
was 10-50 μM. Moreover, our compounds accelerated desensitization of the
with the IC
values varying from 0.12 to 0.49 μM and decreased the peak amplitude with IC
values varying from 16 to 22 μM. Interestingly, our study revealed that only compounds
(epiandrosterone) and
(dehydroepiandrosterone) were able to cause a significant change in
in 10 μM concentration. Moreover, compounds
(testosterone),
(epitestosterone),
(dihydroandrostenedione), and
(etiocholanedione) did not modulate
up to the concentration of 50 μM. Thus, we conclude that compounds
,
,
, and
may be identified as selective modulators of
. Our results offer new avenues of investigation in the field of drug-like selective modulators of
.