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PubMed2004

Comparative analysis of neonicotinoid binding to insect membranes: I. A structure-activity study of the mode of [3H]imidacloprid displacement in Myzus persicae and Aphis craccivora.

Neonicotinoids bind selectively to insect nicotinic acetylcholine receptors with nanomolar affinity to act as potent insecticides. While the members of the neonicotinoid class have many structural features in common, it is not known whether they also share the same mode of binding to the target receptor. Previous competition studies with [3H]imidacloprid, the first commercialised neonicotinoid, indicated that thiamethoxam, representing a novel structural sub-class, may bind in a different way from that of other neonicotinoids. In the present work we analysed the mode of [3H]imidacloprid displacement by established neonicotinoids and newly synthesized analogues in the aphids Myzus persicae Sulzer and Aphis craccivora Koch. We found two classes of neonicotinoids with distinct modes of interference with [3H]imidacloprid, described as direct competitive inhibition and non-competitive inhibition, respectively. Competitive neonicotinoids were acetamiprid, nitenpyram, thiacloprid, clothianidin and nithiazine, whereas thiamethoxam and the N-methyl analogues of imidacloprid and clothianidin showed non-competitive inhibition. The chloropyridine or chlorothiazole heterocycles, the polar pharmacophore parts, such as nitroimino, cyanoimino and nitromethylene, and the cyclic or acyclic structure of the pharmacophore were not relevant for the mode of inhibition. Consensus structural features of the neonicotinoids were defined for the two mechanisms of interaction with [3H]imidacloprid binding. Furthermore, two sub-classes of non-competitive inhibitors can be discriminated on the basis of their Hill coefficients for imidacloprid displacement. We conclude from the present data that the direct competitors share the binding site with imidacloprid, whereas non-competitive compounds, like thiamethoxam, bind to a different site or in a different mode.

Anabasine↗

PubMed2006

Resistance and cross-resistance to neonicotinoid insecticides and spinosad in the Colorado potato beetle, Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae).

The Colorado potato beetle, Leptinotarsa decemlineata (Say), has developed resistance to many insecticides used for its control, recently including imidacloprid, a neonicotinoid compound. Other neonicotinoids are now being deployed to control this pest. A key point in the strategies of resistance management is the monitoring of resistance and cross-resistance. In the summer of 2003, imidacloprid-resistant adult Colorado potato beetles collected from Long Island, New York, USA were bioassayed using topical applications of imidacloprid and nine other neonicotinoids. Compared to a standard susceptible strain, the Long Island beetles showed 309-fold resistance to imidacloprid, and lower levels of cross-resistance to all other neonicotinoids, despite these never having been used in the field, i.e., 59-fold to dinotefuran, 33-fold to clothianidin, 29-fold to acetamiprid, 28-fold to N-methylimidacloprid, 25-fold to thiacloprid, 15-fold to thiamethoxam, 10-fold to nitenpyram, but less than 2-fold to nicotine. In injection bioassays, high resistance to imidacloprid was also found (116-fold). Piperonyl butoxide partially suppressed resistance to imidacloprid, but the resistance level was still over 100-fold, indicating that other mechanisms were primarily responsible for resistance. Low levels of resistance (8- to 10-fold) were found to the nicotinic activator, spinosad, in an imidacloprid-resistant strain collected from the same field in 2004. The cross-resistance seen with all the neonicotinoids tested suggests that the rotation of imidacloprid with other neonicotinoids may not be an effective long-term resistance management strategy. Rotation with spinosad also carries some risk, but it is unlikely that spinosad resistance in this case is mechanistically related to that for the neonicotinoids.

Anabasine↗

PubMed2002

Effects of mutations of a glutamine residue in loop D of the alpha7 nicotinic acetylcholine receptor on agonist profiles for neonicotinoid insecticides and related ligands.

1. Neonicotinoid insecticides are agonists of insect nicotinic acetylcholine receptors (AChRs) and show selective toxicity for insects over vertebrates. To elucidate the molecular basis of the selectivity, amino acid residues influencing neonicotinoid sensitivity were investigated by site-directed mutagenesis of the chicken alpha7 nicotinic AChR subunit, based on the crystal structure of an ACh binding protein (AChBP). 2. In the ligand binding site of AChBP, Q55 in loop D is close to Y164 in loop F that corresponds to G189 of the alpha7 nicotinic receptor. Since Q55 of AChBP is preserved as Q79 in the alpha7 nicotinic receptor and the G189D and G189E mutations have been found to reduce the neonicotinoid sensitivity, we investigated effects of Q79E, Q79K and Q79R mutations on the neonicotinoid sensitivity of the alpha7 receptor expressed in Xenopus laevis oocytes to evaluate contributions of the glutamine residue to nicotinic AChR-neonicotinoid interactions. 3. The Q79E mutation markedly reduced neonicotinoid sensitivity of the alpha7 nicotinic AChR whereas the Q79K and Q79R mutations increased sensitivity, suggesting electronic interactions of the neonicotinoids with the added residues. 4. By contrast, the Q79E mutation scarcely influenced responses of the alpha7 nicotinic receptor to ACh, (-)-nicotine and desnitro-imidacloprid (DN-IMI), an imidacloprid derivative lacking the nitro group, whereas the Q79K and Q79R mutations reduced the sensitivity to these ligands. The results indicate that the glutamine residue of the alpha7 nicotinic receptor is likely to be located close to the nitro group of the insecticides in the nicotinic receptor-insecticide complex.

Amino Acid Sequence↗

PubMed2005

Resistance of insect pests to neonicotinoid insecticides: current status and future prospects.

The first neonicotinoid insecticide introduced to the market was imidacloprid in 1991 followed by several others belonging to the same chemical class and with the same mode of action. The development of neonicotinoid insecticides has provided growers with invaluable new tools for managing some of the world's most destructive crop pests, primarily those of the order Hemiptera (aphids, whiteflies, and planthoppers) and Coleoptera (beetles), including species with a long history of resistance to earlier-used products. To date, neonicotinoids have proved relatively resilient to the development of resistance, especially when considering aphids such as Myzus persicae and Phorodon humuli. Although the susceptibility of M. persicae may vary up to 20-fold between populations, this does not appear to compromise the field performance of neonicotinoids. Stronger resistance has been confirmed in some populations of the whitefly, Bemisia tabaci, and the Colorado potato beetle, Leptinotarsa decemlineata. Resistance in B- and Q-type B. tabaci appears to be linked to enhanced oxidative detoxification of neonicotinoids due to overexpression of monooxygenases. No evidence for target-site resistance has been found in whiteflies, whereas the possibility of target-site resistance in L. decemlineata is being investigated further. Strategies to combat neonicotinoid resistance must take account of the cross-resistance characteristics of these mechanisms, the ecology of target pests on different host plants, and the implications of increasing diversification of the neonicotinoid market due to a continuing introduction of new molecules.

Animals↗

PubMed2005

Assessment of cross-resistance potential to neonicotinoid insecticides in Bemisia tabaci (Hemiptera: Aleyrodidae).

Laboratory bioassays were carried out with four neonicotinoid insecticides on multiple strains of Bemisia tabaci (Gennadius) to evaluate resistance and cross-resistance patterns. Three imidacloprid-resistant strains and field populations from three different locations in the southwestern USA were compared in systemic uptake bioassays with acetamiprid, dinotefuran, imidacloprid and thiamethoxam. An imidacloprid-resistant strain (IM-R) with 120-fold resistance originally collected from Imperial Valley, California, did not show cross-resistance to acetamiprid, dinotefuran or thiamethoxam. The Guatemala-resistant strain (GU-R) that was also highly resistant to imidacloprid (RR=109-fold) showed low levels of cross-resistance when bioassayed with acetamiprid and thiamethoxam. However, dinotefuran was more toxic than either imidacloprid or thiamethoxam to both IM-R and GU-R strains as indicated by low LC50s. By contrast, a Q-biotype Spanish-resistant strain (SQ-R) of B. tabaci highly resistant to imidacloprid demonstrated high cross-resistance to the two related neonicotinoids. Field populations from Imperial Valley (California), Maricopa and Yuma (Arizona), showed variable susceptibility to imidacloprid (LC50s ranging from 3.39 to 115 microg ml(-1)) but did not exhibit cross-resistance to the three neonicotinoids suggesting that all three compounds would be effective in managing whiteflies. Yuma populations were the most susceptible to imidacloprid. Dinotefuran was the most toxic of the four neonicotinoids against field populations. Although differences in binding at the target site and metabolic pathways may influence the variability in cross-resistance patterns among whitefly populations, comparison of whitefly responses from various geographic regions to the four neonicotinoids indicates the importance of ecological and operational factors on development of cross-resistance to the neonicotinoids.

Animals↗

PubMed2002

Toxicological and mechanistic studies on neonicotinoid cross resistance in Q-type Bemisia tabaci (Hemiptera: Aleyrodidae).

The tobacco whitefly, Bemisia tabaci Gennadius (Homoptera: Aleyrodidae) is a serious pest in numerous cropping systems and has developed a high degree of resistance against several chemical classes of insecticides. One of the latest group of insecticides introduced to the market were the neonicotinoids (chloronicotinyls), acting agonistically on insect nicotinic acetylcholine receptors. Resistance to neonicotinoid insecticides has recently been shown to occur, especially in Q-type B tabaci in some places in Almeria, Spain, whereas control of B-type B tabaci in many other intense cropping systems worldwide has remained on high levels. Our study revealed that neonicotinoid-resistant Q-type strains from Almeria were often more than 100-fold less susceptible to thiamethoxam, acetamiprid and imidacloprid when tested in discontinuous systemic laboratory bioassays. The resistance factors were generally 2- to 3-fold lower in leaf-dip bioassays. In addition to the Spanish strains, we obtained two other highly neonicotinoid-cross-resistant B tabaci greenhouse populations, one from Italy (December 1999) and one from Germany (June 2001). A molecular diagnostic analysis revealed that both strains also belong to the (Spanish) subtype Q of the B tabaci species complex. The resistance levels of Q-type whitefly strains derived from Almeria greenhouses in 1999 remained stable for at least two years, even when maintained in the laboratory without any selection pressure. The biochemical mechanisms conferring resistance to neonicotinoids have not yet been elucidated in detail, but synergist studies suggested a possible involvement of microsomal monooxygenases. Furthermore, we checked two Almerian strains of B tabaci isolated in 1998 and 1999 and demonstrated that neonicotinoid resistance is not due to an altered [3H]imidacloprid binding site of nicotinic acetylcholine receptors.

Animals↗

PubMed2006

A nicotinic acetylcholine receptor mutation (Y151S) causes reduced agonist potency to a range of neonicotinoid insecticides.

Neonicotinoid insecticides are potent selective agonists of insect nicotinic acetylcholine receptors (nAChRs). Since their introduction in 1991, resistance to neonicotinoids has been slow to develop, but it is now established in some insect field populations such as the planthopper, Nilaparvata lugens, a major rice pest in many parts of Asia. We have reported recently the identification of a target-site mutation (Y151S) within two nAChR subunits (Nlalpha1 and Nlalpha3) from a laboratory-selected field population of N. lugens. In the present study, we have examined the influence of this mutation upon the functional properties of recombinant nAChRs expressed in Xenopus oocytes (as hybrid nAChRs, co-expressed with a rat beta2 subunit). The agonist potency of several nicotinic agonists has been examined, including all of the neonicotinoid insecticides that are currently licensed for either crop protection or animal health applications (acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid and thiamethoxam). The Y151S mutation was found to have no significant effect on the maximal current (I(max)) observed with the endogenous agonist, acetylcholine. In contrast, a significant reduction in I(max) was observed for all neonicotinoids (the I(max) for mutant nAChRs ranged from 13 to 81% of that observed on wild-type receptors). In addition, nAChRs containing the Y151S mutation caused a significant rightward shift in agonist dose-response curves for all neonicotinoids, but of varying magnitude (shifts in EC(50) values ranged from 1.3 to 3.6-fold). The relationship between neonicotinoid structure and their potency on nAChRs containing the Y151S target-site mutation is discussed.

Acetylcholine↗

PubMed2005

Identification of aldehyde oxidase as the neonicotinoid nitroreductase.

Imidacloprid (IMI), the prototypical neonicotinoid insecticide, is used worldwide for crop protection and flea control on pets. It is both oxidatively metabolized by cytochrome P450 enzymes and reduced at the nitroguanidine moiety by a previously unidentified cytosolic "neonicotinoid nitroreductase", the subject of this investigation. Two major metabolites are detected on incubation of IMI with rabbit liver cytosol: the nitrosoguanidine (IMI-NO) and the aminoguanidine (IMI-NH2). Three lines of evidence identify the molybdo-flavoenzyme aldehyde oxidase (AOX, EC 1.2.3.1) as the neonicotinoid nitroreductase. First, classical AOX electron donor substrates (benzaldehyde, 2-hydroxypyrimidine, and N-methylnicotinamide) dramatically increase the rate of formation of IMI metabolites. Allopurinol and diquat are also effective electron donors, while NADPH and xanthine are not. Second, AOX inhibitors (potassium cyanide, menadione, and promethazine) inhibit metabolite formation when N-methylnicotinamide is utilized as an electron donor. Without the addition of an electron donor, rabbit liver cytosol reduces IMI only to IMI-NO at a slow rate. This reduction is also inhibited by potassium cyanide, menadione, and promethazine, as well as by additional AOX inhibitors, cimetidine and chlorpromazine. Finally, IMI nitroreduction by AOX is sensitive to an aerobic atmosphere, but to a much lesser extent than cytochrome P450 2D6. Large species differences are observed in the IMI nitroreductive activity of liver cytosol. While rabbit and monkey (Cynomolgus) give the highest levels of total metabolite formation, human, mouse, cow, and rat also metabolize IMI rapidly. In contrast, dog, cat, and chicken liver cytosols do not reduce IMI at appreciable rates. AOX, as a neonicotinoid nitroreductase, may limit the persistence of IMI, and possibly other neonicotinoids, in mammals.

Aldehyde Oxidase↗

PubMed1996

Novel neonicotinoid-agarose affinity column for Drosophila and Musca nicotinic acetylcholine receptors.

Neonicotinoids such as the insecticide imidacloprid (IMI) act as agonists at the insect nicotinic acetylcholine receptor (nAChR). Head membranes of Drosophila melanogaster and Musca domestica have a single high-affinity binding site for [3H]IMI with KD values of 1-2 nM and Bmax values of 560-850 fmol/mg of protein. Locusta and Periplaneta nAChRs isolated with an alpha-bungarotoxin (alpha-BGT)-agarose affinity column are known to be alpha-subunit homooligomers. This study uses 1-[N-(6-chloro-3-pyridylmethyl)-N-ethyl]amino-1-amino-2-nitroethene++ + (which inhibits [3H]IMI binding to Drosophila and Musca head membranes at 2-3 nM) to develop a neonicotinoid-agarose affinity column. The procedure-introduction of Triton-solubilized Drosophila or Musca head membranes into this neonicotinoid-based column, elution with IMI, and analysis by lithium dodecyl sulfate-polyacrylamicle gel electrophoresis-gives only three proteins (69, 66, and 61 kDa) tentatively assigned as putative subunits of the nAChR; the same three proteins are obtained with Musca using the alpha-BGT-agarose affinity column. Photoaffinity labeling of the Drosophila and Musca putative subunits from the neonicotinoid column with 125I-alpha-BGT-4-azidosalicylic acid gives a labeled derivative of 66-69 kDa. The yield is 2-5 micrograms of receptor protein from 1 g of Drosophila or Musca heads. Neonicotinoid affinity chromatography to isolate native Drosophila and Musca receptors will facilitate studies on the structure and function of insect nAChRs.

Animals↗

PubMed2002

Selective toxicity of neonicotinoids attributable to specificity of insect and mammalian nicotinic receptors.

Neonicotinoids, the most important new class of synthetic insecticides of the past three decades, are used to control sucking insects both on plants and on companion animals. Imidacloprid (the principal example), nitenpyram, acetamiprid, thiacloprid, thiamethoxam, and others act as agonists at the insect nicotinic acetylcholine receptor (nAChR). The botanical insecticide nicotine acts at the same target without the neonicotinoid level of effectiveness or safety. Fundamental differences between the nAChRs of insects and mammals confer remarkable selectivity for the neonicotinoids. Whereas ionized nicotine binds at an anionic subsite in the mammalian nAChR, the negatively tipped ("magic" nitro or cyano) neonicotinoids interact with a proposed unique subsite consisting of cationic amino acid residue(s) in the insect nAChR. Knowledge reviewed here of the functional architecture and molecular aspects of the insect and mammalian nAChRs and their neonicotinoid-binding site lays the foundation for continued development and use of this new class of safe and effective insecticides.

Alkaloids↗

PubMed2005

Neonicotinoids show selective and diverse actions on their nicotinic receptor targets: electrophysiology, molecular biology, and receptor modeling studies.

Neonicotinoid insecticides, which act selectively on insect nicotinic acetylcholine receptors (nAChRs), are used worldwide for insect pest management. Studies that span chemistry, biochemistry, molecular biology, and electrophysiology have contributed to our current understanding of the important physicochemical and structural properties essential for neonicotinoid actions as well as key receptor residues contributing to the high affinity of neonicotinoids for insect nAChRs. Research to date suggests that electrostatic interactions and possibly hydrogen bond formation between neonicotinoids and nAChRs contribute to the selectivity of these chemicals. A rich diversity of neonicotinoid-nAChR interactions has been demonstrated using voltage-clamp electrophysiology. Computational modeling of nAChR-imidacloprid interaction has assisted in the interpretation of these results.

Amino Acid Motifs↗

PubMed2003

Identification of biochemical markers linked to neonicotinoid cross resistance in Bemisia tabaci (Hemiptera: Aleyrodidae).

The whitefly, Bemisia tabaci (Hemiptera: Aleyrodidae), is a serious pest in many cropping systems world-wide and occurs in different biotypes. The most widespread one is the B-type, whereas the Q-biotype is nowadays still mostly restricted to Southern Spain. Neonicotinoid cross-resistance is known at a high level in Q-types from Spain and individual samples collected in Italy and Germany. Now we detected for the first time high neonicotinoid cross-resistance in a B-type from Israel. Target site resistance to imidacloprid using [(3)H]imidacloprid in nicotinic acetylcholine receptor (nAChR) binding assays could not be detected in any of these highly resistant strains. The impact of metabolizing enzymes such as esterases, glutathione S-transferases, and cytochrome P450-dependent monooxygenases in neonicotinoid resistance was studied biochemically with artificial substrates. Monooxygenase activity was increased 2-3-fold in moderately resistant strains (RF approximately 30) and even 5-6-fold in highly resistant strains (RF approximately 1,000). Only monooxygenase activity correlated with imidacloprid, thiamethoxam and acetamiprid resistance and, therefore, monooxygenases seem to be the only enzyme system responsible for neonicotinoid resistance in B. tabaci Q- and B-types. The oxidative degradation of imidacloprid in resistant Q-type strains could be confirmed by metabolism studies of [(14)C]imidacloprid in vivo. Five-hydroxy-imidacloprid could be detected as the only main metabolite. The insecticidal activity and binding affinity to nAChR of this compound was 10 times lower than imidacloprid itself in B. tabaci.

Animals↗

PubMed2003

Variation in response to neonicotinoid insecticides in peach-potato aphids, Myzus persicae (Hemiptera: Aphididae).

Laboratory bioassays applying the neonicotinoid insecticides imidacloprid, acetamiprid and nitenpyram against clones of the peach-potato aphid Myzus persicae (Sulzer) demonstrated that these compounds effectively circumvent the known carboxylesterase, modified acetylcholinesterase (MACE) and knock-down (kdr) insecticide resistance mechanisms in this species. However, some clones showed cross-tolerance (up to 18-fold) of these compounds relative to susceptible standards. A survey assessing the frequency of neonicotinoid tolerance in M persicae in the UK, based on samples collected from the field and glasshouses between 1997 and 2000, showed that such tolerance is still rare. Experiments on neonicotinoid-susceptible and -tolerant populations of M persicae under simulated field conditions in the laboratory showed that, although the latter were well controlled by imidacloprid applied at recommended application rates, they were more likely to survive and reproduce when this compound was applied at lower concentrations. Such conditions are probably periodically present in imidacloprid-treated field and glasshouse crops. Selection favouring tolerant forms of M persicae could lead to increases in their frequency and the evolution of more potent resistance to neonicotinoids.

Anabasine↗

PubMed2003

The discovery of dinotefuran: a novel neonicotinoid.

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).

Acetylcholine↗

PubMed2004

Comparative analysis of neonicotinoid binding to insect membranes: II. An unusual high affinity site for [3H]thiamethoxam in Myzus persicae and Aphis craccivora.

Neonicotinoids represent a class of insect-selective ligands of nicotinic acetylcholine receptors. Imidacloprid, the first commercially used neonicotinoid insecticide, has been studied on neuronal preparations from many insects to date. Here we report first intrinsic binding data of thiamethoxam, using membranes from Myzus persicae Sulzer and Aphis craccivora Koch. In both aphids, specific binding of [3H]thiamethoxam was sensitive to temperature, while the absolute level of non-specific binding was not affected. In M persicae, binding capacity (Bmax) for [3H]thiamethoxam was ca 450 fmol mg(-1) of protein at 22 degrees C and ca 700 fmol mg(-1) of protein at 2 degrees C. The negative effect of increased temperature was reversible and hence not due to some destructive process. The affinity for [3H]thiamethoxam was less affected by temperature: Kd was ca 11 nM at 2 degrees C and ca 15 nM at 22 degrees C. The membranes also lost binding sites for [3H]thiamethoxam during prolonged storage at room temperature, and upon freezing and thawing. In A craccivora, [3H]thiamethoxam was bound with a capacity of ca 1000 fmol mg(-1) protein and an affinity of ca 90 nM, as measured at 2 degrees C. Overall, the in vitro temperature sensitivity of [3H]thiamethoxam binding was in obvious contrast to the behaviour of [3H]imidacloprid studied in parallel. Moreover, the binding of [3H]thiamethoxam was inhibited by imidacloprid in a non-competitive mode, as shown with M persicae. In our view, these differences demonstrate that thiamethoxam and imidacloprid, which represent different structural sub-classes of neonicotinoids, do not share the same binding site or mode. This holds also for other neonicotinoids, as we report in a companion article.

Anabasine↗

PubMed2006

Substrate specificity of rabbit aldehyde oxidase for nitroguanidine and nitromethylene neonicotinoid insecticides.

The nitroguanidine or nitromethylene moiety of the newest major class of insecticides, the neonicotinoids, is important for potency at insect nicotinic receptors and selectivity relative to mammalian receptors. Aldehyde oxidase (AOX) was recently identified as the imidacloprid nitroreductase of mammalian liver, producing both nitrosoguanidine and aminoguanidine metabolites. The present study considers the ability of AOX, partially purified from rabbit liver, to reduce five commercial nitroguanidine (i.e., imidacloprid, thiamethoxam, clothianidin, and dinotefuran) and nitromethylene (i.e., nitenpyram) neonicotinoid insecticides and three derivatives thereof (i.e., the N-methyl and nitromethylene analogues of imidacloprid and desmethylthiamethoxam). LC/MS/MS was used to demonstrate that AOX reduces nitroguanidines to both nitroso- and aminoguanidines, while nitromethylenes are reduced only to the corresponding nitroso metabolites. Additionally, nitrosonitenpyram was found to spontaneously dehydrate to form a 2-cyanoamidine metabolite, mimicking a predominant photoreaction. The substrate specificity of AOX was characterized as follows: Neonicotinoids with a tertiary nitrogen (N-methylimidacloprid and thiamethoxam) are poor substrates; nitroguanidines are metabolized faster than nitromethylenes; and clothianidin is the most rapidly reduced. Kinetic constants were measured for reduction of three nitroguanidines at two concentrations of AOX. At 2 mg protein/mL, only nitroso metabolites were detected, with Km values of 1.03, 2.99, and 2.41 mM and Vmax values of 5.13, 2.54, and 0.98 nmol/min/mg protein measured for clothianidin, imidacloprid, and dinotefuran, respectively. At 5 mg protein/mL, both amino and nitroso metabolites were detected. However, with each nitroguanidine, the formation of nitroso metabolites did not saturate at substrate levels up to 4 mM, whereas amino metabolite formation exhibited Km values of 0.052, 0.16, and 0.084 mM with corresponding Vmax values of 0.80, 1.24, and 0.79 nmol/min/mg protein for clothianidin, imidacloprid, and dinotefuran, respectively. These in vitro observations show large structural differences in the rates of AOX-catalyzed reduction and help to interpret the extensive studies on in vivo metabolism of neonicotinoid insecticides.

Aldehyde Oxidase↗

PubMed2000

Insect nicotinic acetylcholine receptor: conserved neonicotinoid specificity of [(3)H]imidacloprid binding site.

The insect nicotinic acetylcholine receptor (nAChR) is a major target for insecticide action. The rapidly expanding use of neonicotinoid insecticides of varied structures makes it increasingly important to define similarities and differences in their action, particularly for the first-generation chloropyridinyl compounds versus the second-generation chlorothiazolyl derivatives. We have shown with Musca domestica that a convenient and relevant determination of the neonicotinoid insecticide target is a binding site assay with [(3)H]imidacloprid ([(3)H]IMI). This study uses membranes from the aphids MYZUS: persicae and Aphis craccivora and from heads of the flies Drosophila melanogaster and Musca domestica to characterize the [(3)H]IMI binding sites relative to their number and possible species variation in structure-activity relationships. With emphasis on commercial neonicotinoids, six potent chloropyridinyl compounds are compared with the corresponding six chlorothiazolyl analogues (syntheses are given for chemicals prepared differently than previously described). The preference for chloropyridinyl versus chlorothiazolyl is not dependent on the insect species examined but instead on other structural features of the molecule. The chlorothiazolyl substituent generally confers higher potency in the clothianidin and desmethylthiamethoxam series and the chloropyridinyl moiety in the imidacloprid, thiacloprid, acetamiprid, and nitenpyram series. Two chlorothiazolyl compounds compete directly with the chloropyridinyl [(3)H]IMI for the same binding sites in Myzus and Drosophila membranes. This study shows conserved neonicotinoid specificity of the [(3)H]IMI binding site in each of the four insect species examined.

Amino Acid Sequence↗

PubMed2005

Neonicotinoid insecticide toxicology: mechanisms of selective action.

The neonicotinoids, the newest major class of insecticides, have outstanding potency and systemic action for crop protection against piercing-sucking pests, and they are highly effective for flea control on cats and dogs. Their common names are acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. They generally have low toxicity to mammals (acute and chronic), birds, and fish. Biotransformations involve some activation reactions but largely detoxification mechanisms. In contrast to nicotine, epibatidine, and other ammonium or iminium nicotinoids, which are mostly protonated at physiological pH, the neonicotinoids are not protonated and have an electronegative nitro or cyano pharmacophore. Agonist recognition by the nicotinic receptor involves cation-pi interaction for nicotinoids in mammals and possibly a cationic subsite for interaction with the nitro or cyano substituent of neonicotinoids in insects. The low affinity of neonicotinoids for vertebrate relative to insect nicotinic receptors is a major factor in their favorable toxicological profile.

Animals↗