title: Noncompetitive antagonist-binding sites of rat and housefly gamma-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 gamma-aminobutyric acid (GABA) receptors, at their binding site were investigated using rat brain and housefly head membranes. The (S)-(-)-isomer of TBIPPS (IC50 = 398 nM) was more potent than was the (R)-(+)-isomer of TBIPPS (IC50 = 1220 nM) in rat receptors, while the potencies of (S)-TBIPPS 104 nM) and (R)-TBIPPS (IC50 = 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.
authors.affiliation: Department of Life Science and Biotechnology, Shimane University, Matsue, Japan.
authors.forename: X L
authors.initials: XL
authors.lastname: Ju
authors.forename: Y
authors.initials: Y
authors.lastname: Ozoe
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000648:ultrastructure; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D006793:Houseflies; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D063086:Organothiophosphates / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051381:Rats; D018079:Receptors, GABA / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: C422183:4-tert-butyl-3-isopropyl-2,6,7-trioxa-1-phosphabicyclo(2.2.2)octane 1-sulfide; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018755:GABA Agonists; D009943:Organophosphorus Compounds; D063086:Organothiophosphates; D018079:Receptors, GABA