Entropy as the predominant driving force of binding to human recombinant alpha(x)beta(3)gamma(2) GABA(A) receptors.
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.
Maksay
G
G
Department of Molecular Pharmacology, Chemical Research Centre, Hungarian Academy of Sciences, H-1525 POB 17, Budapest, Hungary. maksay@cric.chemres.hu
McKernan
R
R
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
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