Hiroyuki Hishinuma

Shimane University, Matsu, Shimane Prefecture, Japan

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Publications (2)4.71 Total impact

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    ABSTRACT: Bicyclophosphorothionates (2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-sulfides) are blockers (or non-competitive antagonists) of gamma-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. 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 nM) among the analogues tested, while the 4-cyclohexylbicyclophosphorothionate showed the highest affinity for rat GABA receptors (IC(50) = 125 nM). 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. 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.
    No preview · Article · Sep 2010 · Pest Management Science
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    ABSTRACT: The present study was undertaken to identify noncompetitive γ-aminobutyric acid receptor (GABAR) antagonists that are effective in nematodes, as well as to examine the hypothesis that the noncompetitive antagonism of the GABAR underlies the nematocidal activity of quassinoids against free-living nematodes of the Diplogastridae family. First, 14 known GABAR antagonists were screened for the effectiveness of their nematocidal activity in Diplogastridae. As a result, 3-isopropyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane 1-sulfides (3-isopropyl-BPTs) were found to have high nematocidal activities, and 4-cyclohexyl-3-isopropyl-BPT (23) and 3-isopropyl-4-(2-propenyl)-BPT (27) were the two most potent analogues; these compounds are equipotent to samaderine B and more potent than the anthelmintic abamectin. 23-resistant nematodes, selected by challenge with 23, showed cross-resistance to samaderine B. 23 (10 μM) reduced [3H]23 binding to nematode membranes by 30.4%. Samaderine B (10 μM) resulted in a similar level of the inhibition, but had neither additive nor synergistic effects on the 23 inhibition of [3H]23 binding. These findings suggest that samaderine B shares a common binding site with the GABAR antagonist 23 in Diplogastridae. The results of comparative molecular field analysis, a method of three-dimensional quantitative structure–activity relationship analysis, supported this conclusion.
    No preview · Article · Mar 2005 · Pesticide Biochemistry and Physiology