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The ability of androstane and androstene neurosteroids with modifications at C-17, C-5, and C-3 (compounds  1 - 9 ) to influence the functional activity of inhibitory glycine and γ-aminobutyric acid (GABA) receptors was estimated. The glycine- and GABA-induced chloride current ( I  Gly  and  I  GABA ) 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  I  Gly  and weakly inhibited  I  GABA . The threshold concentration of neurosteroids inducing effects on  I  Gly  was 0.1 μM, and for effects on  I  GABA  was 10–50 μM. Moreover, our compounds accelerated desensitization of the  I  Gly  with the IC 50  values varying from 0.12 to 0.49 μM and decreased the peak amplitude with IC 50  values varying from 16 to 22 μM. Interestingly, our study revealed that only compounds  4  (epiandrosterone) and  8  (dehydroepiandrosterone) were able to cause a significant change in  I  GABA  in 10 μM concentration. Moreover, compounds  3  (testosterone),  5  (epitestosterone),  6  (dihydroandrostenedione), and  9  (etiocholanedione) did not modulate  I  GABA  up to the concentration of 50 μM. Thus, we conclude that compounds  3 ,  5 ,  6 , and  9  may be identified as selective modulators of  I  Gly . Our results offer new avenues of investigation in the field of drug-like selective modulators of  I  Gly .

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