Dinotefuran (MTI-446: (RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine) is a new neonicotinoid commercialized by Mitsui Chemicals. Research led to this novel neonicotinoid by the removal of the chloropyridine or chlorothiazole ring that had been considered as indispensable for neonicotinoides. The research advanced as follows; (1) selection of acetylcholine for the lead compound, (2) recognition of the insecticidal advantages of 3-methoxypropyl compounds, (3) synthesis of (+/-)-tetrahydro-3-furylmethyl compounds by cyclization of the 3-methoxypropyl moiety. It resulted in dinotefuran which has a (+/-)-tetrahydro-3-furylmethyl moiety instead of a halogenated aromatic heterocyclic ring, and belongs to the third-generation neonicotinoids (sub-class: furanicotinyl compounds).
The planthopper Laodelphax striatellus (Fallén) (Hemiptera: Delphacidae) is a serious insect pest of rice, Oryza sativa L., and has developed resistance to fipronil in Japan. Sequence analysis of L. striatellus RDL gamma-aminobutyric acid (GABA) receptor subunit (LS-RDL) genes from a fipronil-resistant population and a fipronil-susceptible strain identified the A2'N mutation (index number for M2 membrane-spanning region), that was previously implicated in fipronil resistance in the planthopper Sogatella furcifera (Horváth) (Hemiptera: Delphacidae). Nineteen of 21 fipronil-resistant L. striatellus individuals were genotyped as heterozygous for the A2'N mutation, suggesting that this mutation is associated with fipronil resistance and that most fipronil-resistant L. striatellus express wild-type and A2'N mutant LS-RDL simultaneously. To confirm the role of the A2'N mutation of LS-RDL, Drosophila Mel-2 cells were transfected with wild-type and A2'N mutant LS-RDL genes, either individually or together. A membrane potential assay showed that fipronil had no inhibitory effect at 10 microM on cells transfected with the A2'N mutant LS-RDL gene with or without the wild-type LS-RDL gene. By contrast, the IC50 value of fipronil for wild-type LS-RDL homomers was 14 nM. These results suggest that the A2'N mutation of the RDL GABA receptor subunit confers fipronil resistance in L. striatellus as well as S. furcifera.
To investigate the action of dinotefuran (MTI-446, 1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine), a recently developed insecticide, on insect nicotinic acetylcholine receptors (nAChRs), we determined the potencies of the compound and 15 analogues in inhibiting the specific binding of [3H]epibatidine (EPI), a nAChR agonist, and [3H]alpha-bungarotoxin (alpha-BGT), a competitive nAChR antagonist, to the nerve cord membranes of American cockroaches (Periplaneta americana). Racemic dinotefuran inhibited [3H]EPI binding with an IC50 of 890 nM and [3H]alpha-BGT binding with an IC50 of 36.1 microM. Scatchard analysis indicated that the dinotefuran inhibition of [3H]EPI binding was a competitive one. Slight structural modification caused a drastic reduction in potency; only four analogues were found to be equipotent to or more potent than dinotefuran. Chloropyridinyl and chlorothiazolyl neonicotinoid insecticides displayed two or three orders of magnitude higher potency than dinotefuran. There was a good correlation between the IC50 values of tested compounds obtained with [3H]EPI and those obtained with [3H]alpha-BGT. A better correlation was observed between 3-h knockdown activities (KD50) against German cockroaches (Blattella germanica) and IC50 values obtained from [3H]EPI assays than between 24-h lethal activities (LD50) and IC50 values. While the results indicate that dinotefuran and its analogues interact with the ACh-binding site in cockroach nAChRs, it remains to be elucidated why they displayed lower potencies than those expected based on their insecticidal activities.
The whitebacked planthopper Sogatella furcifera is a serious pest of rice that has developed fipronil resistance in Asia. We found a novel R340Q mutation in the cytoplasmic loop between M3 and M4 of the S. furcifera RDL γ-aminobutyric acid (GABA) receptor subunit (SF-RDL). The R340Q mutation was found in clones carrying the A2′N mutation, which was previously implicated in fipronil resistance and suggested to be a heterozygous mutation. To investigate the influence of mutations, Drosophila Mel-2 cells were transfected with wild-type or mutant SF-RDL genes, either individually or together. A membrane potential assay showed that the influence of the A2′N · R340Q double mutation on fipronil resistance was more profound than that of the A2′N single mutation in the heterozygous expression of wild-type and mutant SF-RDL genes.
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