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

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F20%3A00523573" target="_blank" >RIV/61388963:_____/20:00523573 - isvavai.cz</a>

  • Výsledek na webu

    <a href="https://www.frontiersin.org/articles/10.3389/fnmol.2020.00044/full" target="_blank" >https://www.frontiersin.org/articles/10.3389/fnmol.2020.00044/full</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.3389/fnmol.2020.00044" target="_blank" >10.3389/fnmol.2020.00044</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

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

  • Popis výsledku v původním jazyce

    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 (IGly and IGABA) 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 IGly and weakly inhibited IGABA. The threshold concentration of neurosteroids inducing effects on IGly was 0.1 μM, and for effects on IGABA was 10–50 μM. Moreover, our compounds accelerated desensitization of the IGly with the IC50 values varying from 0.12 to 0.49 μM and decreased the peak amplitude with IC50 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 IGABA in 10 μM concentration. Moreover, compounds 3 (testosterone), 5 (epitestosterone), 6 (dihydroandrostenedione), and 9 (etiocholanedione) did not modulate IGABA up to the concentration of 50 μM. Thus, we conclude that compounds 3, 5, 6, and 9 may be identified as selective modulators of IGly. Our results offer new avenues of investigation in the field of drug-like selective modulators of IGly.

  • Název v anglickém jazyce

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

  • Popis výsledku anglicky

    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 (IGly and IGABA) 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 IGly and weakly inhibited IGABA. The threshold concentration of neurosteroids inducing effects on IGly was 0.1 μM, and for effects on IGABA was 10–50 μM. Moreover, our compounds accelerated desensitization of the IGly with the IC50 values varying from 0.12 to 0.49 μM and decreased the peak amplitude with IC50 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 IGABA in 10 μM concentration. Moreover, compounds 3 (testosterone), 5 (epitestosterone), 6 (dihydroandrostenedione), and 9 (etiocholanedione) did not modulate IGABA up to the concentration of 50 μM. Thus, we conclude that compounds 3, 5, 6, and 9 may be identified as selective modulators of IGly. Our results offer new avenues of investigation in the field of drug-like selective modulators of IGly.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    30103 - Neurosciences (including psychophysiology)

Návaznosti výsledku

  • Projekt

    <a href="/cs/project/TN01000013" target="_blank" >TN01000013: Personalizovaná medicína - diagnostika a terapie</a><br>

  • Návaznosti

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Ostatní

  • Rok uplatnění

    2020

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    Frontiers in Molecular Neuroscience

  • ISSN

    1662-5099

  • e-ISSN

  • Svazek periodika

    13

  • Číslo periodika v rámci svazku

    Mar 20

  • Stát vydavatele periodika

    CH - Švýcarská konfederace

  • Počet stran výsledku

    11

  • Strana od-do

    44

  • Kód UT WoS článku

    000525630900001

  • EID výsledku v databázi Scopus

    2-s2.0-85083062307