title: Entropy as the predominant driving force of binding to human recombinant alpha(x)beta(3)gamma(2) GABA(A) receptors.
abstract: In order to study the correlation of the thermodynamic driving forces of binding with the efficacies of displacing ligands, the specific binding of [3H]SR 95531 [2-(3-carboxypropyl)3-amino-6-p-methoxyphenylpyridazinium bromide], a GABA(A) receptor antagonist, was studied in cell lines stably expressing human alpha(1)beta(3)gamma(2) and alpha(2)beta(3)gamma(2) GABA(A) receptors. Displacing potencies for the agonists with different efficacies (muscimol, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and piperidine-4-sulfonic acid) and for antagonists (SR 95531 and 5-(4-piperidyl)isothiazol-3-ol) were determined at 0 degrees C, 20 degrees C and 37 degrees C. Displacing potencies were temperature-nearly independent for alpha(1)beta(3)gamma(2) receptors. At alpha(2)beta(3)gamma(2), receptor binding of the antagonists was exothermic, endothermic for the agonists THIP and piperidine-4-sulfonic acid and isothermic for muscimol. The free energy increments of displacement for the binding of the antagonist [3H]SR 95531 versus the agonist [3H]muscimol approach saturation as a function of the efficacies of the displacers only for alpha(1)beta(3)gamma(2) receptors. This suggests that, for binding to alpha(1)beta(3)gamma(2) GABA(A) receptors, displacement is an efficacy-dependent interaction predominantly driven by entropic increases.
authors.affiliation: Department of Molecular Pharmacology, Chemical Research Centre, Hungarian Academy of Sciences, H-1525 POB 17, Budapest, Hungary. maksay@cric.chemres.hu
authors.forename: G
authors.initials: G
authors.lastname: Maksay
authors.forename: R
authors.initials: R
authors.lastname: McKernan
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019277:Entropy; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D007739:L Cells; D008566:Membranes / Q000378:metabolism; D051379:Mice; D009118:Muscimol / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011724:Pyridazines / Q000378:metabolism / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013696:Temperature; D014316:Tritium
chemical_list: D018755:GABA Agonists; D018756:GABA Antagonists; D007555:Isoxazoles; D010880:Piperidines; D011724:Pyridazines; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D014316:Tritium; C073009:5-(4-piperidyl)isoxazol-3-ol; D009118:Muscimol; C023402:piperidine-4-sulfonic acid; C049853:gabazine; C015542:gaboxadol