Effects of Gabaergic Phenols on Phospholipid Bilayers as Evaluated by <sup>1</sup>H-NMR

Abstract

The phenols propofol and thymol, and lately carvacrol, eugenol and chlorothymol, have been shown to act as positive allosteric modulators on GABA A receptor, which is the main inhibitory receptor of the central nervous system. GABA A receptor is an intrinsic membrane protein which activity may be affected by surface-active compounds and by physical changes in the membrane. Recently, we demonstrated that these phenols interacted with the lipid membrane phase, suggesting their anesthetic activity could be the combined result of their specific (with receptor proteins) as well as nonspecific (with surrounding lipid molecules) interaction modulating the supramolecular organization of the receptor environment. In the current study, by using 1 H-NMR spectroscopy, we have investigated the effects of the insertion and the possible preferential location of the five phenol derivatives with GABAergic activity on EPC membranes. The results indicate that all compounds are able to insert in EPC phospholipid vesicles and to locate in the region between the polar group (choline molecule), the glycerol and the first atoms of the acyl chains, being the more lipophilic compounds (propofol and chlorothymol) that seem to prefer a deeper bilayer insertion. The location of the phenol molecules would reduce the repulsive forces among phospholipids head groups allowing closer molecular packing and finally diminishing the mobility of the hydrocarbon chains, as revealed by 1 H spin relaxation times.

Preparation and characterization of clove essential oil-loaded liposomes

“…The authors reported the localization of these phenols in the region between the polar groups (choline molecule), the glycerol backbone and the first atoms of the acyl chains. This localization reduced the repulsive forces among the phospholipid head groups, thus decreasing the mobility of the hydrocarbon chains, as revealed by 1 H spin relaxation times (Reiner et al, 2013). So, Eug may not diffuse from the lipid bilayer to the surrounding aqueous phase (Fujisawa et al, 1988); this may explain the increase in the vesicle size (Tables 1 and 2).…”

“…Although the effect of eugenol on lipid bilayer properties has previously been studied (Fujisawa, Kadoma, & Komoda, 1988;Manabe, Nakayama, & Sakamoto, 1987;Pandey, Lathika, & Mishra, 2006;Reiner, Fraceto, De Paula, Perillo, & Garcia, 2013), our study is the first to deal with the encapsulation of eugenol and CEO in lipid vesicles. Besides, the effect of phospholipid type on the vesicle characteristics is also studied.…”

The interaction of eugenol with cell membrane models at the air–water interface is modulated by the lipid monolayer composition

“…The location of the drug in the lipid membrane is an important issue, being discussed in the literature for liposomes. Reiner et al [26] suggested that eugenol is able to insert in egg phosphatidylcholines, being located in the region between the polar groups, with the glycerol and first atoms of the acyl chain. This can reduce the repulsive forces among the lipid head groups, permitting closer molecular packing and decreasing the mobility of hydrocarbon chains, as revealed by 1 H-NMR.…”

Comparative Interactions of Anesthetic Alkylphenols with Lipid Membranes

“…Membrane fluidity, curvature, elasticity and dipolar arrangement modulate the receptor-mediated interactions between drugs and membranes [31]. The anesthetic effects of alkylphenols are referred to as the combined results of their interactions with receptor or channel proteins and those with membrane lipids to modify the lipid environments surrounding such functional proteins [32].…”