A molecular model for the synergic interaction between GABA and general anesthetics

Item does not contain fulltext Within the context of the discussion about rational polytherapy, we determined the effects of four anaesthetics on the binding of [H-3]t-butylbicycloorthobenzoate ([H-3]TBOB) to the GABA(A) receptor complex in the presence of several concentrations of GABA (gamma-aminobutyric acid), in order to build a molecular model that can describe and quantify the interactions between the compounds. The empirical isobole method revealed that GABA and the anaesthetics acted synergically in displacing [H-3]TBOB. This synergy could be described by a simple molecular model in which both GABA and the anaesthetics displaced [H-3]TBOB allosterically and in which GABA allosterically enhanced the binding of the anaesthetics. To get information about the interaction between GABA and anaesthetics, we used [H-3]TBOB as a tracer ligand. The model indicated that GABA enhanced the affinity of thiopental 3.0-fold, propofol 5.0-fold, the neuroactive steroids Org 20599 3.5-fold and Org 20549 13-fold. Insight into the molecular mechanism and strength of these interactions can help clinicians to choose therapeutically optimal drug and dose combinations: a step towards rational polytherapy.