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Physicochemical and biological properties of novel amide-based steroidal inhibitors of NMDA receptors
SK. Adla, B. Slavikova, M. Smidkova, E. Tloustova, M. Svoboda, V. Vyklicky, B. Krausova, P. Hubalkova, M. Nekardova, K. Holubova, K. Vales, M. Budesinsky, L. Vyklicky, H. Chodounska, E. Kudova,
Language English Country United States
Document type Journal Article
Persistent link
https://www.medvik.cz/link/bmc17031495
Grant support
NV15-29370A
MZ0
CEP Register
- MeSH
- Amides MeSH
- Hep G2 Cells MeSH
- Caco-2 Cells MeSH
- Blood-Brain Barrier drug effects metabolism MeSH
- Humans MeSH
- Magnetic Resonance Spectroscopy MeSH
- Molecular Structure MeSH
- Neurotransmitter Agents chemistry pharmacology MeSH
- Reactive Oxygen Species metabolism MeSH
- Receptors, N-Methyl-D-Aspartate antagonists & inhibitors metabolism MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Herein, we report a new class of amide-based inhibitors (1-4) of N-methyl-d-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 1.4μM, respectively) as compared with endogenous inhibitor - pregnanolone sulfate (IC50=24.6μM) and pregnanolone glutamate (IC50=51.7μM); (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.
References provided by Crossref.org
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- $a Herein, we report a new class of amide-based inhibitors (1-4) of N-methyl-d-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 1.4μM, respectively) as compared with endogenous inhibitor - pregnanolone sulfate (IC50=24.6μM) and pregnanolone glutamate (IC50=51.7μM); (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.
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- $a Slavikova, Barbora $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Prague 6 - Dejvice, 166 10, Czech Republic.
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- $a Vyklicky, Vojtech $u Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic.
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- $a Nekardova, Michaela $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Prague 6 - Dejvice, 166 10, Czech Republic; Faculty of Mathematics and Physics, Charles University in Prague, Ke Karlovu 3, Prague 2, 121 16, Czech Republic.
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- $a Holubova, Kristina $u Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic.
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- $a Vyklicky, Ladislav $u Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic.
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- $a Kudova, Eva $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Prague 6 - Dejvice, 166 10, Czech Republic. Electronic address: kudova@uochb.cas.cz.
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