title: Distributions of therapeutically promising neurosteroids in cellular membranes.
abstract: 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.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 16610 Prague 6, Czech Republic; Faculty of Science, Charles University in Prague, Viničná 5, 128 44 Prague 2, Czech Republic.
authors.forename: Kamila
authors.initials: K
authors.lastname: Riedlová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 16610 Prague 6, Czech Republic; Faculty of Mathematics and Physics, Charles University in Prague, Ke Karlovu 3, Prague 2, 121 16, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nekardová
authors.affiliation: University of Chemistry and Technology, Technicka 5, 16610 Prague 6, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Kačer
authors.affiliation: University of Chemistry and Technology, Technicka 5, 16610 Prague 6, Czech Republic.
authors.forename: Kamila
authors.initials: K
authors.lastname: Syslová
authors.affiliation: Rudjer Bošković Institute, Division of Organic Chemistry and Biochemistry, POB 180, HR-10002 Zagreb, Croatia.
authors.forename: Mario
authors.initials: M
authors.lastname: Vazdar
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 16610 Prague 6, Czech Republic; Department of Physics, Tampere University of Technology, P. O. Box 692, FI-33101 Tampere, Finland.
authors.forename: Pavel
authors.initials: P
authors.lastname: Jungwirth
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 16610 Prague 6, Czech Republic. Electronic address: kudova@uochb.cas.cz.
authors.forename: Eva
authors.initials: E
authors.lastname: Kudová
authors.affiliation: J. Heyrovský Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, Dolejškova 3, 182 23 Prague, Czech Republic. Electronic address: lukasz.cwiklik@jh-inst.cas.cz.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Cwiklik
mesh_terms: D002462:Cell Membrane / Q000737:chemistry*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D018377:Neurotransmitter Agents / Q000737:chemistry*; D010539:Permeability; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D018377:Neurotransmitter Agents
keywords: Chromatography; Membranes; Molecular dynamics; N-Methyl-d-aspartate receptors; Steroids