Mode neonicotinoids

Many pesticides are not as novel as they may seem. Some, such as the pyre-throid and neonicotinoid insecticides, are modeled on natural insecticides. Synthetic pyrethroids are related to the natural pyrethrins (see Chapter 12), whereas the neo-nicotinoids share structural features with nicotine. In both cases, the synthetic compounds have the same mode of action as the natural products they resemble. Also, the synthetic pyrethroids are subject to similar mechanisms of metabolic detoxication as natural pyrethrins (Chapter 12). More widely, many detoxication mechanisms are relatively nonspecific, operating against a wide range of compounds that... 

Most importantly, the chart indicates how two classes with new modes of action, the neonicotinoids and strobilurins, both introduced in the last decade, continue to stimulate the market, suggesting that a focus on new modes of action remains an excellent recipe for success. 

Neonicotinoids, Bioinformatics, an initio Chemistry, Binding Mode, Nitromethene, Tetrahydro-pyridine, QSAR, Cross-Resistance... 

Univ., China) presented his recent research results entitled Structure-activity relationship of novel sulfonylurea inhibitors on AHAS . H. Matsumoto (Univ. of Tsukuba, Japan) then introduced his study Mode of action of several classes of herbicides causing photooxi dative injury in plants . The second one dealt with insecticides, where X.-H. Qian (East China Univ. of Science and Technology, China) and K. Matsuda (Kinki Univ., Japan) presented their recent findings on chemistry and biochemistry of neonicotinoids. Interchange between Pesticide Science Societies of Korea and Japan was also maintained at a seminar entitled Current and future R D activities in agrochemical area in Korea and Japan . 

These data showed that thiamethoxam (13), like imidadoprid (8) and the other neonicotinoids, binds with high affinity to nicotinic receptors [57]. However, there are clear differences to the other commercial neonicotinoids, as documented by a kinetic analysis of competition experiments [56]. While [ H]thiamethoxam (13) binds to receptors with nanomolar affinity, micromolar concentrations are required to displace [ H]imidadoprid (8). Further, the interaction between the two compounds is non-competitive , meaning that binding of thiamethoxam (13) reduces the binding capacity of the receptor preparation for imidadoprid (8) but not its affinity. Thiamethoxam (13) shares this unusual mode of inhibition with other neonicotinoids (not commercialized) containing a N-methyl group as pharmacophore substituent [56, 58]. 

In summary, varied and minor structural differences in neonicotinoid molecules may confer diversity in their binding modes, depending upon insect spedes and may explain the unique receptor binding behavior of thiamethoxam (13) [56-58] as well as of dinotefiiran [64]. 

Neonicotinoids are insecticides acting on insect nAChRs (1). For a long time they are very effective on commercially important Hemipteran pest species such as aphids, whiteflies and planthoppers, but also control Coleopteran and some Lepidopteran pests (/). The biochemical mode of action (MoA) of neonicotinoids has been studied and characterized extensively in the past 10 years. Ail neonicotinoids act selectively as agonists at the insect nAChRs and they are part of a single MoA group as defmed by the Insecticide Resistance Action Committee (IRAC an Expert Conunittee of Crop Life) for resistance management purposes (2). Today the neonicotinoids are ... 

Thiamethoxam High-Affinity Binding and Unusual Mode of Interference with Other Neonicotinoids at Aphid Membranes... 

Neonicotinoids do not act as a homogenous class of insecticides. Radioligand receptor binding assays revealed two classes of neonicotinoids described here as competitive and non-competitive , respectively, relative to [ H]imidacloprid. Differences in affinity, mode of displacement, number of binding sites and temperature sensitivity suggest that thiamethoxam binds in a way unique among the commercial neonicotinoids. Metabolic transformation is not relevant for its insecticidal effects. 

Neonicotinoid insecticides have experienced a most remarkable and steady increase in use since their market introduction in 1991, now exceeding 10% of the total insecticide market 1-3). An overview of these products is given in Table I (cf. 4). The major advantages of the new products over the previously preferred organophosphates are a novel chemistry, a new mode of action, systemic action and human safety. The systemic activity makes them the insecticide class of choice for the control of plant sucking pests. 

Different Modes of Binding Interaction with Other Neonicotinoids... 

In extending the determinations of IC50 values for displacement potencies of competitors we analyzed in detail also their mode of displacement of [ H]imidacloprid (5). As a most remarkable result, we identified two types of displacement of the labeled compound, which we described as competitive and non-competitive , respectively (Figure 1 Table III). Non-competitive displacement of [ HJimidacloprid was found with thiamethoxam and a number of other neonicotinoids that were all characterized by a common structural feature, namely an iV-Methyl group in the pharmacophore. 

As thiamethoxam is the only iV-Methyl compound on the market, its noncompetitive behavior contrasted to all other commercial neonicotinoids, which all displayed a competitive mode. The A -Methyl rule was not plicable to acetamiprid, thiacloprid and nithiazine (no tyical neonicotinoid) a possible interpretation has been given in a recent publication (S). 

Table III. The Two Classes of Neonicotinoids as Defined by Their Mode of Displacement of [ imidacloprid...

In conclusion, temperature affects binding of thiamethoxam as well as imidacloprid in a reversible way, though the former compound is clearly stronger affected. This also suggests that the binding modes or sites of the two neonicotinoids at the target receptor are obviously not identical. 

As effects like those documented for thiamethoxam have not yet been described in the receptor binding field, the results, though based on thorough and self-critical experimentation, may be questioned. In our view, these novel results necessarily call for novel interpretations. A most evident conclusion from the present results is that binding of thiamethoxam has a different impact (as measurable in binding assays) on the receptor complex as binding of other, competitive neonicotinoids. Whether this different mode of interaction is due... 

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