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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,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
Grantová podpora
NV15-29370A
MZ0
CEP - Centrální evidence projektů
- MeSH
- amidy MeSH
- buňky Hep G2 MeSH
- Caco-2 buňky MeSH
- hematoencefalická bariéra účinky léků metabolismus MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární struktura MeSH
- neurotransmiterové látky chemie farmakologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- receptory N-methyl-D-aspartátu antagonisté a inhibitory metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články 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.
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- $a Adla, Santosh Kumar $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. $7 gn_A_00001809
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- $a Physicochemical and biological properties of novel amide-based steroidal inhibitors of NMDA receptors / $c 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,
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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 Tloustova, 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.
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- $a Svoboda, Martin $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 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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