Neonicotinoid insecticides nAChRs

Imidacloprid is a widely used neonicotinoid insecticide that kills pests by targeting their central nAChRs. Levamisol is used to kill nematodes by acting on nAChRs in the worm s muscles. 

Neonicotinoids are potent broad-spectrum insecticides that exhibit contact, stomach and systemic activity. Acetamiprid, imidacloprid, nitenpyram, thiamethoxam and thiacloprid are representatives of the neonicotinoid insecticides (Figure 1). The mechanism of action is similar to that of nicotine, acting on the central nervous system causing irreversible blocking of postsynaptic nicotinic acetylcholine receptors (nAChR). Neonicotinoid insecticides are often categorized as antagonists of the... 

In a recent study, resistance to the neonicotinoid insecticide, imidacloprid, in the brown plant hopper, Nilaparvata lugens, was found to be due to a point mutation at a conserved position in two nAChR subunits. As a result, it reduced the receptor binding of imidacloprid (Liu et al., 2005). 

Generally, insect nAChRs clearly vary with specificity of their interaction with neonicotinoid insecticides however, the appropriate subunit is unclear so far. An investigation that supports the hypothesis that there is a conserved neonicotinoid special sensitive subtype of the nAChR binding site in different insects like Musca domestica, D. melanogaster, Aphis craccivora, Myzus persicae has been discussed [97]. 

Neonicotinoid insecticides are more than 100-fold selective for insect nAChRs over vertebrate nAChRs, but little is known about the mechanism of selectivity... 

In contrast to S-(—)-nicotine (1 rat oral LD50 = 50-60 mg a.i. kg , high mammalian oral and dermal toxicity), neonicotinoid insecticides display excellent selectivity profiles that are largely attributable to spedfity for insect versus vertebrate nAChRs. This is exemplified by the fact that the radioligand [ H]-7 serves... 

Neonicotinoid insecticides act agonistically on insect nicotinic acetylcholine receptors (nAChRs). Like imidacloprid (IMI), all neonicotinoids bind with high affinity (Iso-values 1 nM) to binding sites on... 

Understanding the selectivity of neonicotinoids toward insect nAChR is essential for environment protection, human health, and insecticide resistance [7], and also a key issue for the design and structure-relationship of new derivatives. 

The cholinergic system in insects is the main target of insecticides. One class of molecules, the neonicotinoids, induces direct activation of the neuronal nicotinic acetylcholine receptors (nAChRs). In the honey bee these receptors are mainly distributed in the olfactory pathways that link sensory neurons to antennal lobes and mushroom bodies. These structures seem to play an important role in olfactory conditioning. We have previously shown that cholinergic antagonists injected in different parts of the brain impaired the formation and retrieval of olfactory memory. We then advanced the hypothesis that, through the activation of the nAChR, the neonicotinoid imidacloprid (IMI) would lead to facilitation of the memory trace. 

Efforts have been made to develop insecticides with high affinity to the nAChR, resulting in the development of nereistoxin analogues (e.g., 3-5), neonicotinoids (e.g., 7-13) and spinosyns (e.g., 15). 

Since the discovery of 7, diverse imidacloprid-related insecticides referred to as neonicotinoids have been synthesized. Like 7, all commercial neonicotinoids 8-13 bind with high affinity (I50 1 mM) to [ H]-7 binding sites on insect nAChRs. 

These examples indicate the complexity of insect nAChRs, which is difficult to understand. The considerable diversity of potential subunit combinations probably accounts for the multiplicity of distinctive pharmacological profiles in insect nAChRs. In that context, electrophysiology will play an essential role in determining the significance of certain subunit combinations in the MoA of neonicotinoid and further insecticidally active ligands. 

Comparing the structures of nicotine and epibatidine to the first neonicotinoid, imidacloprid, one may suspect the example of a consequent further development of a highly potent lead compound from the natural products pool (Fig. 8.42). This is indeed not the case. Nicotine has been used as an insecticide for more than a hundred years. However, Izuru Yamamoto s structure variations in the 1960s did not result in any promising active substances. [135] Epibatidine, the nAChR agonist from a poisonous frog skin, which could have served as a pharmacophore template, had still not been discovered at the time when neonicotinoids were being developed. 

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 ... 

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