Article date: 2001/1/4
PubMed ID: 11137858
Journal name: European journal of pharmacology (ISSN: 0014-2999)
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.
Author List: Maksay G, McKernan R
Publication Types: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't
Substances mentioned in the article: GABA Agonists; GABA Antagonists; Isoxazoles; Piperidines; Pyridazines; Receptors, GABA-A; Recombinant Proteins; Tritium; 5-(4-piperidyl)isoxazol-3-ol; Muscimol; piperidine-4-sulfonic acid; gabazine; gaboxadol;
Mesh terms: Animals; Binding, Competitive/drug effects; Dose-Response Relationship, Drug; Entropy; GABA Agonists/pharmacology; GABA Antagonists/pharmacology; Humans; Isoxazoles/pharmacology; L Cells (Cell Line); Membranes/metabolism; Mice; Muscimol/metabolism; Piperidines/pharmacology; Pyridazines/metabolism; Receptors, GABA-A/genetics; Recombinant Proteins/metabolism; Temperature; Tritium;