Neonicotinoids different

Karmakar, R., Singh, S.B., and Kulshrestha, G., Persistence and transformation of thiamethoxam, a neonicotinoid insecticide, in soil of different agroclimatic zones of India, Bull. Environ. Contam. Toxicol, 76,400, 2006. 

Nicotine and neonicotinoids are agonists, both of which act at the nicotinic acetylcholine receptor -Na" /K+ ionophore. The structural differences between the insect and mammalian receptors define the selectivity of neonicotinoid toxicity to insects and nicotine toxicity to vertebrates. The proposed concept of the neonicotinoid electronegative pharmacophore... 

Researchers had proposed some residues that may contribute to the selectivity through mutation experiments [8-10], Here, through bioinformatic and statistical analysis, residue distribution differences in the ligand binding sites between arthropods and vertebrates as well as features of nicotinic leads were studied. The specihc sites that contribute to the neonicotinoids selectivity were identified and coincide well with the known experimental data. 

Selectivity of neonicotinoids. The differences between arthropods and vertebrates nAChR are clearly revealed. The pocket environments of vertebrates nAChR are... 

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. 

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]. 

For example, in 1970 a useful nicotinic pharmacophore model was already described by Beers and Reich and subsequently improved by Sheridan et al. [103]. Starting from different models a distance from the onium group to a point on the van der Waals surface of the H-bond acceptor of 5.9 A was common to several ligands. Up to now three binding models of neonicotinoids have been proposed (cf Fig. 29.1.2) [104]. 

Electrophysiological evidence indicates that spinosyns can alter nicotinic currents in neuronal cell bodies from CNS of the American cockroach [P. americana (L)j. The effect is correlated with toxicity to neonate Heliothis virescens larvae. It can be su ested that the spinosyns affect nAChR and GABA receptors through a so-called undetermined mecdianism and differ from that of neonicotinoids... 

Fig. 29.1.3. Whole cell current responses of a neurone isolated from the CNS of Heliothis virescens after application of different neonicotinoids. The dose-response curve was fitted by the Hill equation. All currents were first normalized to mean amplitudes elicited b)/10 pM ACh before and after each test concentration was applied and then normalized to the relative amplitude elicited...

All of these act as agonists on the nAChR, but the potency and agonistic efficacy of each of these neonicotinoids were quite different. The five-membered imidacloprid (7) and the open-chain clothianidin (12) were the most potent neonicotinoids in this Heliothis preparation with an EC50 of 0.3 pM (Table 29.1.4). 

Table 29.1.4 Comparison between electro-physiological and [ H]-7 displacement potencies for different neonicotinoids 6-9, 13 and ( )-epibatidin (16) on insect nAChRs. Electrophysiological data [ECso and relative (agonist) efficacy] were obtained from neuron cell bodies isolated from the CNS of H. virescens. EC50 and relative efficacy values represent the mean of separate experiments on different neurons. Inhibition of [ H]-7 binding to nAChR in housefly head membrane preparations by the compounds is expressed as piso (piso values (= -log M) correspond to the concentration of cold ligand displacing 50% of bound [ H]-7 from housefly head membranes).

Fig. 29.1.4. Comparison between electro-physiological and binding potencies of different neonicotinoids (6-9) and nicotinoids. Electrophysiological data were obtained from neurone cell bodies isolated from the CNS of H. virescens. pECsoS (= -log M) correspond to the half-...

Table 29.1.5 Displacement of [ H]-7 by different neonicotinoids 7-12 from nAChR preparations from housefly head membranes, expressed as Iso in nM (this represents the concentration needed to displace half of the radioligand from its binding site).

In general, all commercialized neonicotinoids can be divided into open-chain compounds (Chapter 29.2.1) and neonicotinoids having ring systems such as five-membered (Chapter 29.2.2) and six-membered compounds (Chapter 29.2.3) that differ in their molecular characteristics. The structural requirements for both neonicotinoids having open-chain stmctures and ring-system containing neonicotinoids consist of different segments Usted below (Fig. 29.2.1, Tables 29.2.1 and 29.2.2) [1, 2]. 

The subdivision of commercialized neonicotinoids into different generations implies their ranking regarding novelty - a view not based on chemical or biochemical classification. The I RAC classification places all neonicotinoids in group 4A. 

Taiget Sites in the Nervous System Neonicotinoids target nicotinic acetylcholine receptors, as has mainly been demonstrated by studies with imidadoprid (8). Compared with imidadoprid and the other neonicotinoid sales products, thiame-thoxam (13) binds in a different way, possibly to a different site of the receptor in aphids [55-58]. 

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]. 

In addition to haemolymph sample analyses, whole larvae of S. frugiperda were homogenized in order to determine the proportion of THIAM 6, CLOTHI 8 and iV-desmethyl THIAM 9 at two different time intervals. Just four hours after oral dosing of 1 pg THIAM 6 30% of neonicotinoid equivalents in larvae represent CLOTHI 8. From the biological point of view, this small amount of CLOTHI 8 should be sufficient for the strong insecticidal activity observed after oral application of THIAM 6 (Figure 6). 

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. 

While members of the neonicotinoid class of insecticides share a number of structural and physico-chemical properties, the individual compounds provide a remarkable diversity of structural details, which may confer biological differences in their action 13). 

Regarding the structural features of neonicotinoids, the pharmacophore part is characterized by a polar group represented by eidier a nitro group or a cyano group 13). Based on neighboring structural differences in the pharmacophore and on the heterocycle that typically is aromatic and mono-substituted by chlorine, neonicotinoids can be grouped as presented in Table II. 

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