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Synthesis and structure–activity relationship analysis of bicyclophosphorothionate blockers with selectivity for housefly γ‐aminobutyric acid receptor channels
Author(s) -
Ju XiuLian,
Fusazaki Sayaka,
Hishinuma Hiroyuki,
Qiao Xiaomu,
Ikeda Izumi,
Ozoe Yoshihisa
Publication year - 2010
Publication title -
pest management science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.296
H-Index - 125
eISSN - 1526-4998
pISSN - 1526-498X
DOI - 10.1002/ps.1973
Subject(s) - housefly , receptor , chemistry , selectivity , gabaa receptor , stereochemistry , biochemistry , pharmacology , biology , musca , botany , larva , catalysis
Abstract BACKGROUND: Bicyclophosphorothionates (2,6,7‐trioxa‐1‐phosphabicyclo[2.2.2]octane‐1‐sulfides) are blockers (or non‐competitive antagonists) of γ‐aminobutyric acid (GABA) receptor channels. Twenty‐two bicyclophosphorothionates with different 3‐ and 4‐substituents were synthesised, and [ 3 H]4′‐ethynyl‐4‐ n ‐propylbicycloorthobenzoate (EBOB) binding assays were performed to evaluate their affinities for housefly and rat GABA receptors. RESULTS: Introduction of an isopropyl group at the 3‐position enhanced the affinity of bicyclophosphorothionates for housefly GABA receptors and reduced the affinity towards rat GABA receptors. The 4‐isopentyl‐3‐isopropylbicyclophosphorothionate showed the highest affinity for housefly GABA receptors (IC 50 = 103 n M ) among the analogues tested, while the 4‐cyclohexylbicyclophosphorothionate showed the highest affinity for rat GABA receptors (IC 50 = 125 n M ). Among the bicyclophosphorothionates synthesised to date, the former analogue exhibited the highest selectivity for housefly GABA receptors, with an IC 50 rat /IC 50 fly ratio of approximately 97. Three‐dimensional GABA receptor models successfully explained the structure–activity relationships of the bicyclophosphorothionates. CONCLUSION: The results indicate that minor structural modifications of blockers can change their selectivity for insect versus mammalian GABA receptors. The substituent at the 3‐position of the bicyclophosphorothionates dictates selectivity for housefly versus rat GABA receptors. This information should prove useful for the design of safer insecticides and parasiticides. Copyright © 2010 Society of Chemical Industry