Noncompetitive antagonist-binding sites of rat and housefly γ-aminobutyric acid receptors display different enantiospecificities for tert-butyl(isopropyl)bicyclophosphorothionate

Abstract

The enantiomers of 4- tert-butyl-3-isopropyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane 1-sulfide (TBIPPS) were prepared in nine steps from diethyl tert-butylmalonate, and their abilities to compete with [ 3H]1-(4-ethynylphenyl)-4- n-propyl-2,6,7-trioxabicyclo[2.2.2]octane (EBOB), a noncompetitive antagonist of ionotropic γ-aminobutyric acid (GABA) receptors, at their binding site were investigated using rat brain and housefly head membranes. The ( S)-(−)-isomer of TBIPPS (IC 50=398 nM) was more potent than was the ( R)-(+)-isomer of TBIPPS (IC 50=1220 nM) in rat receptors, while the potencies of ( S)-TBIPPS (IC 50=104 nM) and ( R)-TBIPPS (IC 50=94.4 nM) in housefly receptors were almost the same. The different enantiospecificities of rat and housefly receptors indicate that the three-dimensional structure of the binding site might be different between these receptors. In a region of the rat binding site there might be a steric bulk that interacts less favorably with ( R)-TBIPPS than with ( S)-TBIPPS, while in the corresponding region of the housefly binding site there might not be such a steric bulk that leads to specificity for these compounds.