Physicochemical and biological properties of novel amide-based steroidal inhibitors of NMDA receptors

0474432 - ÚOCHB 2018 RIV US eng J - Článek v odborném periodiku
Adla, Santosh Kumar - Slavíková, Barbora - Šmídková, Markéta - Tloušťová, Eva - Svoboda, Martin - Vyklický, Vojtěch - Krausová, Barbora - Hubálková, Pavla - Nekardová, Michaela - Holubová, Kristína - Valeš, Karel - Buděšínský, Miloš - Vyklický ml., Ladislav - Chodounská, Hana - Kudová, Eva
Physicochemical and biological properties of novel amide-based steroidal inhibitors of NMDA receptors.
Steroids. Roč. 117, Jan (2017), s. 52-61. ISSN 0039-128X. E-ISSN 1878-5867.
[Conference on Isoprenoids /23./. Minsk, 04.09.2016-07.09.2016]
Grant CEP: GA TA ČR(CZ) TE01020028; GA ČR(CZ) GAP303/12/1464; GA MŠMT LO1302; GA MZd(CZ) NV15-29370A; GA ČR(CZ) GBP208/12/G016
Institucionální podpora: RVO:61388963 ; RVO:67985823
Klíčová slova: neurosteroid * NMDA receptor * structure-activity relationship * amide * blood-brain-barrier permeability * Caco-2 assay
Obor OECD: Organic chemistry; Organic chemistry (FGU-C)
Impakt faktor: 2.523, rok: 2017

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.
Trvalý link: http://hdl.handle.net/11104/0271487