Membrane interaction of natural ciclic ketones with inhibitory activity on the GABAA receptor

SANCHEZ BORZONE, M; DELGADO MARÍN, L; GARCIA, DA

Córdobs

Congreso; 3º Reunión Internacional de Ciencias Farmacéuticas (RICiFa 2014).; 2014

The GABAA receptor (GABA-R) is the main inhibitory receptor of the Central Nervous System. It possesses binding sites for drugs other than the neurotransmitter GABA, including benzodiazepines, barbiturates, and the convulsant picrotoxine which behave as allosteric modulators or channel blockers. The study of this last site is especially relevant since it constitutes the action site of widely used neurotoxic organochlorine pesticides. Our group has studied some cyclic ketones, structurally similar to the convulsant product thujone, demonstrating their ability to inhibit the GABA-R activity. Taking into account that all the ketones studied are highly lipophilic, and considering that many compounds that regulate GABA-R function are noticeably lipophilic, which may change the physical properties of the lipid bilayer, in the present work we studied the effect of five cyclic ketones (including the reference compound thujone) on the microviscosity of artificial membranes by fluorescence anisotropy. These studies were completed with the analysis of the cytotoxic activity of these compounds by using a test that evaluates the membrane integrity (LDH test). The results showed that all the ketones included in this research were able to modify the membrane microviscosity incrementing the probes mobility. However, the LDH studies indicated that only one compound showed cytotoxic effect at higher concentrations and longer exposure times. Concluding, all compounds are able to interact with the membrane modifying its properties, although in biological systems the cell could to respond to these changes to maintain the membrane integrity.