Detail
Article
Online article
FT
Medvik - BMC
  • Something wrong with this record ?

Positive Modulators of the N-Methyl-d-aspartate Receptor: Structure-Activity Relationship Study of Steroidal 3-Hemiesters

B. Krausova, B. Slavikova, M. Nekardova, P. Hubalkova, V. Vyklicky, H. Chodounska, L. Vyklicky, E. Kudova,

. 2018 ; 61 (10) : 4505-4516. [pub] 20180504

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc19028457

Grant support
NV15-29370A MZ0 CEP Register

Here, we report the synthesis of pregn-5-ene and androst-5-ene dicarboxylic acid esters and explore the structure-activity relationship (SAR) for their modulation of N-methyl-d-aspartate receptors (NMDARs). All compounds were positive modulators of recombinant GluN1/GluN2B receptors (EC50 varying from 1.8 to 151.4 μM and Emax varying from 48% to 452%). Moreover, 10 compounds were found to be more potent GluN1/GluN2B receptor modulators than endogenous pregnenolone sulfate (EC50 = 21.7 μM). The SAR study revealed a relationship between the length of the residues at carbon C-3 of the steroid molecule and the positive modulatory effect at GluN1/GluN2B receptors for various D-ring modifications. A selected compound, 20-oxo-pregnenolone hemiadipate, potentiated native NMDARs to a similar extent as GluN1/GluN2A-D receptors and inhibited AMPARs and GABAAR responses. These results provide a unique opportunity for the development of new steroid based drugs with potential use in the treatment of neuropsychiatric disorders involving hypofunction of NMDARs.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc19028457
003      
CZ-PrNML
005      
20201031115452.0
007      
ta
008      
190813s2018 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1021/acs.jmedchem.8b00255 $2 doi
035    __
$a (PubMed)29708744
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Krausova, Barbora $u Institute of Physiology of the Czech Academy of Sciences , Videnska 1083 , Prague 4, 142 20 , Czech Republic.
245    10
$a Positive Modulators of the N-Methyl-d-aspartate Receptor: Structure-Activity Relationship Study of Steroidal 3-Hemiesters / $c B. Krausova, B. Slavikova, M. Nekardova, P. Hubalkova, V. Vyklicky, H. Chodounska, L. Vyklicky, E. Kudova,
520    9_
$a Here, we report the synthesis of pregn-5-ene and androst-5-ene dicarboxylic acid esters and explore the structure-activity relationship (SAR) for their modulation of N-methyl-d-aspartate receptors (NMDARs). All compounds were positive modulators of recombinant GluN1/GluN2B receptors (EC50 varying from 1.8 to 151.4 μM and Emax varying from 48% to 452%). Moreover, 10 compounds were found to be more potent GluN1/GluN2B receptor modulators than endogenous pregnenolone sulfate (EC50 = 21.7 μM). The SAR study revealed a relationship between the length of the residues at carbon C-3 of the steroid molecule and the positive modulatory effect at GluN1/GluN2B receptors for various D-ring modifications. A selected compound, 20-oxo-pregnenolone hemiadipate, potentiated native NMDARs to a similar extent as GluN1/GluN2A-D receptors and inhibited AMPARs and GABAAR responses. These results provide a unique opportunity for the development of new steroid based drugs with potential use in the treatment of neuropsychiatric disorders involving hypofunction of NMDARs.
650    _2
$a alosterická regulace $7 D000494
650    _2
$a HEK293 buňky $7 D057809
650    _2
$a lidé $7 D006801
650    _2
$a modulátory membránového transportu $x chemie $x farmakologie $7 D049990
650    _2
$a molekulární modely $7 D008958
650    _2
$a molekulární struktura $7 D015394
650    _2
$a pregnenolon $x farmakologie $7 D011284
650    _2
$a konformace proteinů $7 D011487
650    _2
$a receptory N-methyl-D-aspartátu $x antagonisté a inhibitory $x metabolismus $7 D016194
650    _2
$a steroidy $x chemie $x farmakologie $7 D013256
650    _2
$a vztahy mezi strukturou a aktivitou $7 D013329
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Slavikova, Barbora $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences , Flemingovo nam. 2 , Prague 6, 166 10 , Czech Republic.
700    1_
$a Nekardova, Michaela $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences , Flemingovo nam. 2 , Prague 6, 166 10 , Czech Republic. Faculty of Mathematics and Physics , Charles University in Prague , Ke Karlovu 3 , Prague 2, 121 16 , Czech Republic.
700    1_
$a Hubalkova, Pavla $u Institute of Physiology of the Czech Academy of Sciences , Videnska 1083 , Prague 4, 142 20 , Czech Republic. Third Faculty of Medicine , Charles University in Prague , Ruska 87 , Prague 10, 100 00 , Czech Republic.
700    1_
$a Vyklicky, Vojtech $u Institute of Physiology of the Czech Academy of Sciences , Videnska 1083 , Prague 4, 142 20 , Czech Republic.
700    1_
$a Chodounska, Hana $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences , Flemingovo nam. 2 , Prague 6, 166 10 , Czech Republic.
700    1_
$a Vyklicky, Ladislav $u Institute of Physiology of the Czech Academy of Sciences , Videnska 1083 , Prague 4, 142 20 , Czech Republic.
700    1_
$a Kudova, Eva $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences , Flemingovo nam. 2 , Prague 6, 166 10 , Czech Republic.
773    0_
$w MED00010049 $t Journal of medicinal chemistry $x 1520-4804 $g Roč. 61, č. 10 (2018), s. 4505-4516
856    41
$u https://pubmed.ncbi.nlm.nih.gov/29708744 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20190813 $b ABA008
991    __
$a 20201031115450 $b ABA008
999    __
$a ok $b bmc $g 1433606 $s 1066917
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2018 $b 61 $c 10 $d 4505-4516 $e 20180504 $i 1520-4804 $m Journal of medicinal chemistry $n J Med Chem $x MED00010049
GRA    __
$a NV15-29370A $p MZ0
LZP    __
$a Pubmed-20190813

Find record

Citation metrics

Archiving options