A molecular model for the synergic interaction between gamma-aminobutyric acid and general anaesthetics

Within the context of the discussion about rational polytherapy, we determi ned the effects of four anaesthetics on the binding of [H-3]t-butylbicycloo rthobenzoate ([H-3]TBOB) to the GABA(A) receptor complex in the presence of several concentrations of GABA (gamma-aminobutyric acid), in order to buil d a molecular model that can describe and quantify the interactions between the compounds. The empirical isobole method revealed that GABA and the ana esthetics acted synergically in displacing [H-3]TBOB. This synergy could be described by a simple molecular model in which both GABA and the anaesthet ics displaced [H-3]TBOB allosterically and in which GABA allosterically enh anced the binding of the anaesthetics. To get information about the interac tion between GABA and anaesthetics, we used [H-3]TBOB as a tracer ligand. T he 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 2054 9 13-fold. Insight into the molecular mechanism and strength of these inter actions can help clinicians to choose therapeutically optimal drug and dose combinations: a step towards rational polytherapy. (C) 1999 Elsevier Scien ce B.V. All rights reserved.