title: A molecular model for the synergic interaction between gamma-aminobutyric acid and general anaesthetics.
abstract: Within the context of the discussion about rational polytherapy, we determined the effects of four anaesthetics on the binding of [3H]t-butylbicycloorthobenzoate ([3H]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 [3H]TBOB. This synergy could be described by a simple molecular model in which both GABA and the anaesthetics displaced [3H]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 [3H]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.
authors.affiliation: NICI/Department Psychology, University of Nijmegen, HE Nijmegen, The Netherlands. rijn@nici.kun.nl
authors.forename: C M
authors.initials: CM
authors.lastname: Van Rijn
authors.forename: E
authors.initials: E
authors.lastname: Willems-van Bree
authors.forename: J P
authors.initials: JP
authors.lastname: Zwart
authors.forename: J F
authors.initials: JF
authors.lastname: Rodrigues de Miranda
authors.forename: R
authors.initials: R
authors.lastname: Dirksen
mesh_terms: D000495:Allosteric Site; D018681:Anesthetics, General / Q000378:metabolism*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D066298:In Vitro Techniques; D008958:Models, Molecular; D016548:Prosencephalon / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018681:Anesthetics, General; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C046308:tert-butylbicyclo-2-benzoate