Gabergic phenols are capable to modulate lipid phase transition resembling propofol behavior.

MIGUEL V; SANCHEZ BORZONE, M; GARCIA DA

Tucumán,

Congreso; III Latin American Federation of Biophysical Societies (LAFeBS).; 2016

Soc Arg de Biofísica

GABAAreceptor (GABA-R) is the main inhibitory receptor of the central nervous system.Its ligands include drugs other than the GABA neurotransmitter, such asbenzodiazepines, barbiturates, anesthetics, ethanol and the convulsantpicrotoxinin, which behave as allosteric modulators or channel blockers. Thereis still considerable debate about molecular mechanisms by which general anestheticsinduce sedation. Since many lipophilic compounds that regulate GABA-R functioncan change the physical properties of the lipid bilayer, it is expected that thereceptor could be modulated not only by the specific ligand recognition, butalso by changes in the physical state of the membrane. Previous experimentalresults from our group have demonstrated that the intravenous anestheticpropofol, and other derived phenols with gabaergic activity, are able tointeract with membranes. NMR, fluorescence anisotropy and Langmuir filmsstudies indicated that they locate in the region between the polar group andthe first atoms of the acyl chains of phospholipid membranes (1). In thepresent work, we obtained spatially resolved free energy profiles of propofoland GABAergic phenol`s partition into DPPC bilayers. These profiles allowed usto determine the most probable phenols-DPPC interaction site. Also, freediffusion Molecular Dynamics simulations of DPPC in presence of the different phenolswere used to analyze their interaction with a bilayer. These studies revealed atighter packing in the hydrocarbon chains of the DPPC in presence of these compounds.The simulations revealed that GABAergic phenols have a cholesterol-like orderingeffect on DPPC in the fluid phase, as proved before for Propofol (2).