Distributions of therapeutically promising neurosteroids in cellular membranes

0475164 - ÚOCHB 2018 RIV IE eng J - Journal Article
Riedlová, Kamila - Nekardová, Michaela - Kačer, P. - Syslová, K. - Vazdar, M. - Jungwirth, Pavel - Kudová, Eva - Cwiklik, Lukasz
Distributions of therapeutically promising neurosteroids in cellular membranes.
Chemistry and Physics of Lipids. Roč. 203, Mar (2017), s. 78-86. ISSN 0009-3084. E-ISSN 1873-2941
R&D Projects: GA TA ČR(CZ) TE01020028; GA ČR(CZ) GAP303/12/1464; GA ČR GA15-14292S; GA ČR(CZ) GBP208/12/G016
Institutional support: RVO:61388963 ; RVO:61388955
Keywords : steroids * N-methyl-D-aspartate receptors * membranes * molecular dynamics * chromatography
OECD category: Physical chemistry; Physical chemistry (UFCH-W)
Impact factor: 2.766, year: 2017

Interactions of two neurosteroids, inhibiting membrane-bound N-Methyl-D-aspartate receptors, with phospholipid membranes are studied. Namely, endogenous pregnanolone sulfate is compared with pregnanolone glutamate, the latter being a novel synthetic steroidal inhibitor of these receptors with potential pharmaceutical use. Molecular-level details of steroid-phospholipid membranes interactions are scrutinized employing molecular dynamics simulations supported by quantum chemical calculations to assess steroid lipophilicity. Moreover, permeability of both species across membranes is experimentally evaluated by immobilized artificial membrane chromatography. We demonstrate that while there is no significant difference of lipophilicity and membrane permeability between the two steroids, they differ significantly regarding detailed localization in phospholipid membranes. The bulky glutamate moiety of pregnanolone glutamate is flexible and well exposed to the water phase while the sulfate group of pregnanolone sulfate is hidden in the membrane headgroup region. This dissimilarity of behavior in membranes can potentially account for the observed different activities of the two steroids toward membrane-bound N-Methyl-D-aspartate receptors.
Permanent Link: http://hdl.handle.net/11104/0272677