Referenced in: none

Automatically associated channels: Kir2.3

Title: A four-ligand hypercube model to quantify allosteric interactions within the GABAA receptor complex.

Authors: Clementina M van Rijn, Elly Willems-van Bree

Journal, date & volume: Eur. J. Pharmacol., 2004 Feb 6 , 485, 43-51

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/14757122

Abstract
The aim of this study was to investigate the couplings between various binding sites on the GABA(A) receptor complex. We investigated combinations of three test compounds: (1) GABA (gamma-aminobutyric acid), (2) Org 20549 [(2 beta 3 alpha 5 alpha)-21hydroxy-3Hydroxy-2(4morpholinyl)pregnan-20one methane-sulphonate)], a neuroactive steroid and (3) retigabine (D-23129, N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester), a new antiepileptic drug. Receptor-binding assays were conducted using rat brain membranes. [3H]TBOB ([3H]-t-butyl-bicyclo-ortho-benzoate) was the tracer ligand. All three test compounds inhibited the binding of [3H]TBOB with EC(50)'s of 4.0, 98 and 23 microM, respectively. Isobolic analysis of the combination data showed that the three compounds act in synergy in displacing [3H]TBOB. These interactions could be described and quantified by a hypercube model in which each of the three test compounds and [3H]TBOB bind to different, allosterically coupled sites such that each of the test compounds allosterically displaces the tracer [3H]TBOB and allosterically enhances the affinity of any other test compound by a factor 4.4. The simultaneous binding of any two ligands enhances the affinity of the third by a factor 9. These results may contribute to the understanding of individual variability in drug responses and to the discussion about rational polytherapy.