Synthesis and structure-activity relationship analysis of bicyclophosphorothionate blockers with selectivity for housefly [gamma]-aminobutyric acid receptor channels

Bicyclophosphorothionates (2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-sulfides) are blockers (or non-competitive antagonists) of ...-aminobutyric acid (GABA) receptor channels. Twenty-two bicyclophosphorothionates with different 3- and 4-substituents were synthesised, and [...H]4'-ethynyl-4-n...

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Published inPest management science Vol. 66; no. 9; p. 1002
Main Authors Ju, Xiu-Lian, Fusazaki, Sayaka, Hishinuma, Hiroyuki, Qiao, Xiaomu, Ikeda, Izumi, Ozoe, Yoshihisa
Format Journal Article
LanguageEnglish
Published London Wiley Subscription Services, Inc 01.09.2010
Subjects
Insect control
Insecticides
Neurotransmitters
Pest control
Pesticides
Resistance to control
Rodents
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Summary:Bicyclophosphorothionates (2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-sulfides) are blockers (or non-competitive antagonists) of ...-aminobutyric acid (GABA) receptor channels. Twenty-two bicyclophosphorothionates with different 3- and 4-substituents were synthesised, and [...H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) binding assays were performed to evaluate their affinities for housefly and rat GABA receptors. 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... = 103 nM) among the analogues tested, while the 4-cyclohexylbicyclophosphorothionate showed the highest affinity for rat GABA receptors (IC... = 125 nM). Among the bicyclophosphorothionates synthesised to date, the former analogue exhibited the highest selectivity for housefly GABA receptors, with an IC.../IC... ratio of approximately 97. Three-dimensional GABA receptor models successfully explained the structure-activity relationships of the bicyclophosphorothionates. 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. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:1526-498X
1526-4998