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Physicochemical and biological properties of novel amide-based steroidal inhibitors of NMDA receptors
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SYSNO ASEP 0474432 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Physicochemical and biological properties of novel amide-based steroidal inhibitors of NMDA receptors Author(s) Adla, Santosh Kumar (UOCHB-X) ORCID
Slavíková, Barbora (UOCHB-X) RID, ORCID
Šmídková, Markéta (UOCHB-X) RID, ORCID
Tloušťová, Eva (UOCHB-X) RID, ORCID
Svoboda, Martin (UOCHB-X) ORCID
Vyklický, Vojtěch (FGU-C) RID, ORCID, SAI
Krausová, Barbora (FGU-C) ORCID
Hubálková, Pavla (FGU-C)
Nekardová, Michaela (UOCHB-X) RID
Holubová, Kristína (FGU-C) ORCID, SAI, RID
Valeš, Karel (FGU-C) RID, ORCID, SAI
Buděšínský, Miloš (UOCHB-X) RID, ORCID
Vyklický ml., Ladislav (FGU-C) RID, ORCID, SAI
Chodounská, Hana (UOCHB-X) RID, ORCID
Kudová, Eva (UOCHB-X) RID, ORCIDSource Title Steroids. - : Elsevier - ISSN 0039-128X
Roč. 117, Jan (2017), s. 52-61Number of pages 10 s. Action Conference on Isoprenoids /23./ Event date 04.09.2016 - 07.09.2016 VEvent location Minsk Country BY - Belarus Event type WRD Language eng - English Country US - United States Keywords neurosteroid ; NMDA receptor ; structure-activity relationship ; amide ; blood-brain-barrier permeability ; Caco-2 assay Subject RIV CC - Organic Chemistry OECD category Organic chemistry R&D Projects TE01020028 GA TA ČR - Technology Agency of the Czech Republic (TA ČR) GAP303/12/1464 GA ČR - Czech Science Foundation (CSF) LO1302 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) NV15-29370A GA MZd - Ministry of Health (MZ) GBP208/12/G016 GA ČR - Czech Science Foundation (CSF) Institutional support UOCHB-X - RVO:61388963 ; FGU-C - RVO:67985823 UT WOS 000392566800009 EID SCOPUS 84994181912 DOI 10.1016/j.steroids.2016.08.010 Annotation Herein, we report a new class of amide-based inhibitors (1-4) of N-methyl-o-aspartate receptors (NMDARs) that were prepared as analogues of pregnanolone sulfate (PAS) and pregnanolone glutamate (PAG) - the steroidal neuroprotective NMDAR inhibitors. A series of experiments were conducted to evaluate their physicochemical and biological properties: (i) the inhibitory effect of compounds 3 and 4 on NMDARs was significantly improved (IC50 = 1.0 and 1.4 mu M respectively) as compared with endogenous inhibitor - pregnanolone sulfate (IC50 = 24.6 mu M) and pregnanolone glutamate (IC50 = 51.7 mu M), (ii) physicochemical properties (logP and logD) were calculated, (iii) Caco-2 assay revealed that the permeability properties of compounds 2 and 4 are comparable with pregnanolone glutamate, (iv) compounds 1-4 have minimal or no adverse hepatic effect, (v) compounds 1-4 cross blood-brain-barrier. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2018
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