Neonicotinoids potency

The acute toxicity (i.e., lethal potency) of imidacloprid, other neonicotinoids, and related analogs in mammals is most closely related to potency at the 7 nicotinic receptor subtype, followed in order by potency at 1x4, fSx, 0(3, and aj nicotinic receptors, respectively. However, acute toxicity in mammals involves complex actions (agonist and antagonist) at multiple receptor subtypes and these actions vary greatly with minor changes in chemical structure. 

The metabolism of neonicotinoids in vertebrates, insects, and plants has many common features. It may result in cleavage and the separation of the heterocyclic and pharmacophore moieties, or modifications of a pharmacophore in an intact parent molecule. Oxidations, reductions, and elimination reactions are the major mechanisms that result mostly in a reduced or diminished insecticidal potency of the metabolites. Dehydration of the 4-hydroxyimidazolidinyl resulting in a formation of the imidazolinyl (olefin) or reduction of the N-nitroimine ( = N—NO2) to N-nitrosoimine ( = N—NO) group (Figure 5) are examples of a... 

The lead compound, which initiated interest in the neonicotinoids, is a nitro-methylene heterocycle, nithiazine (Figure 1) [1]. Nifhiazine, with its unique nitromethylene moiety, showed low mammalian toxicity, but its insecticidal potency and field stability were inferior to commercial organophosphates and pyrethroids. Thus, nithiazine was not of commercial use for pest control. However, the introduction of 6-choloronicotinyl and 2-nitroimino-imidazolidine moieties led to the development of the first commercial neonicotinoid imidacloprid (Figure 1)... 

A nicotinic acetylcholine receptor point mutation (Y151S) conferring insecticide resistance causes reduced agonist potency to a range of neonicotinoids (N. S. Millar, Univ. College London, UK)... 

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-...

While the plant protection division of Shell was sold to Dupont in 1986, the neonicotinoid research came to a halt. Independently, chemists at Nihon Tok-ushu Noyaku Seizo K. K. (now part of Bayer CropScience) in Japan had begun to modify the nitromethylene lead structure already at the beginning of the 1980s. Among other changes, they replaced the phenyl substituent in 1-ben-zyl-2-(nitromethylene)-imidazolidine by a 2-pyridyl unit, and found that this derivative had comparatively low insecticidal activity. With a 3- or 4-pyridyl substituent, the potency increased however by a factor of around 25. Retrospectively, it became clear why the introduction of a 3-pyridyl residue was so beneficial (Fig. 8.43). [136,137]... 

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. 

In 2003, Kagabu et al. reported on the racemic synthesis of a chiral analog of imidacloprid, the reference compound of the neonicotinoid insecticide family. Although the recently synthesized Me-imidacloprid (rac-35) is less active than imidacloprid, the (5)-35 enantiomer has shown a higher potency than its (R)-counterpart. Backvall et al. developed an asymmetric synthesis leading to the active (5)-enantiomer, which includes a very efficient DKR of the alcohol intermediate rac-32 (Scheme 57.8). " ... 

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