2,6,7-Trioxa-1-phosphabicyclo[2.2.2
]octane 1-sul®des (bicyclophosphorothionates) with various C 1±4 alkyl groups at the 3-and 4-positions were synthesized and tested for their ability to compete with [ 3 H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a non-competitive antagonist of g-aminobutyric acid (GABA) receptors, for speci®c binding to rat-brain and house¯y-head membranes, and for their insecticidal activity against house¯ies. Among the 3,4-substituted analogues, 20 compounds were selectively active for house¯y GABA receptors versus rat GABA receptors. The 3alkyl groups of C 3 length and the 4-alkyl groups of C 4 length were tolerated in house¯y receptors, whereas such bulky substituents were deleterious in rat receptors. The 4-isobutyl-3-isopropyl analogue was the most potent in house¯y receptors (IC 50 = 45.2 nM), and tert-butylbicyclophosphorothionate (TBPS), with the 4-tert-butyl group and no 3-substituent, was the most potent in rat receptors (IC 50 = 62.2 nM). Their receptor selectivities (rat IC 50 /house¯y IC 50 ) were 52 and 0.038, respectively. The insecticidal activity (LD 50 ) of 20 active analogues was well correlated with their potency (IC 50 ) in inhibiting [ 3 H]EBOB binding to house¯y-head membranes (r = 0.93). The results obtained in the present study indicate that the introduction of appropriate alkyl groups into the 3-and 4-positions of bicyclophosphorothionate leads to non-competitive antagonists with increased af®nity and selectivity for house¯y ionotropic GABA receptors versus rat GABA A receptors.