Nematocidal quassinoids and bicyclophosphorothionates: a possible common mode of action on the GABA receptor |
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Authors: | Tadahiko Kuriyama Sayaka Fusazaki Tadaaki Satou Tamotsu Nikaido |
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Institution: | a Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane 690-8504, Japan b Department of Pharmacognosy, School of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan |
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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-trioxabicyclo2.2.2]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. |
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Keywords: | Quassinoids Bicyclophosphorothionates GABA receptor Nematocide Mode of action |
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