0501437 - ÚOCHB 2020 RIV US eng J - Journal Article
Matoušová, Marika - Souček, Radko - Tloušťová, Eva - Slavíková, Barbora - Chodounská, Hana - Mertlíková-Kaiserová, Helena - Kudová, Eva
Pregn-5-en-3beta-ol and androst-5-en-3beta-ol dicarboxylic acid esters as potential therapeutics for NMDA hypofunction: In vitro safety assessment and plasma stability.
Steroids. Roč. 147, Jul (2019), s. 4-9. ISSN 0039-128X. E-ISSN 1878-5867
R&D Projects: GA ČR(CZ) GA17-02300S; GA MZd(CZ) NV15-29370A; GA MŠMT LO1302
Institutional support: RVO:61388963
Keywords : neurosteroid * NMDA receptor hypofunction * hepatotoxicity * mitotoxicity * Caco-2 permeability * plasma stability
OECD category: Neurosciences (including psychophysiology
Impact factor: 1.948, year: 2019
Method of publishing: Limited access
https://www.sciencedirect.com/science/article/abs/pii/S0039128X18301752?via%3Dihub

Neurosteroids are endogenous steroidal compounds that can modulate neuronal receptors. N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that are of particular interest, as they participate in synaptic transmission and are implicated in various processes, such as learning, memory, or long-term neuronal potentiation. Positive allosteric modulators that increase the activity of NMDARs may provide a therapeutic aid for patients suffering from neuropsychiatric disorders where NMDAR hypofunction is thought to be involved, such as intellectual disability, autism spectrum disorder, or schizophrenia. We recently described a new class of pregn-5-ene and androst-5-ene 3β-dicarboxylic acid hemiesters (2–24) as potent positive modulators of NMDARs. Considering the recommended guidelines for the early stage development of new, potent compounds, we conducted an in vitro safety assessment and plasma stability screening to evaluate their druglikeness. First, compounds were screened for their hepatotoxicity and mitochondrial toxicity in a HepG2 cell line. Second, toxicity in primary rat postnatal neurons was estimated. Next, the ability of compounds 2–24 to cross a Caco-2 monolayer was also studied. Finally, rat and human plasma stability screening revealed an unforeseen high stability of the C-3 hemiester moiety. In summary, by using potency/efficacy towards NMDARs data along with toxicity profile, Caco-2 permeability and plasma stability, compounds 14 and 15 were selected for further in vivo animal studies.
Permanent Link: http://hdl.handle.net/11104/0296235