Bicyclophosphorothionate antagonists exhibiting selectivity for housefly GABA receptors
1999
Ju, X.L. | Ozoe, Y.
2,6,7-Trioxa-1-phosphabicyclo[2.2.2] octane 1-sulfides (bicyclophosphorothionates) with various C1-4 alkyl groups at the 3- and 4-positions were synthesized and tested for their ability to compete with [3H]4'-ethynyl-4-n- propylbicycloorthobenzoate (EBOB), a non-competitive antagonist of gamma-aminobutyric acid (GABA) receptors, for specific binding to rat-brain and housefly-head membranes, and for their insecticidal activity against houseflies. Among the 3,4-substituted analogues, 20 compounds were selectively active for housefly GABA receptors versus rat GABA receptors. The 3-alkyl groups of C3 length and the 4-alkyl groups of C4 length were tolerated in housefly receptors, whereas such bulky substituents were deleterious in rat receptors. The 4-isobutyl-3-isopropyl analogue was the most potent in housefly receptors (IC50=45.2nM), and tert-butylbicyclophosphorothionate (TBPS), with the 4-tert-butyl group and no 3-substituent, was the most potent in rat receptors (IC50 = 62.2 nM). Their receptor selectivities (rat IC50/housefly IC50) were 52 and 0.038, respectively. The insecticidal activity (LD50) of 20 active analogues was well correlated with their potency (IC50) in inhibiting [3H]EBOB binding to housefly-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 affinity and selectivity for housefly ionotropic GABA receptors versus rat GABA(A) receptors.
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