Neonicotinoids open-chain

Acetamiprid Nippon Soda Neonicotinoid Open-chain (1995) JV-cyano-... 

SumiTake/[ ] Neonicotinoid Open chain N-Bayer nitroguanidine... 

From the lead structure 2-nitromethylene-tetrahydro-l,3-thiazine (6, nithiazine) [7, 8], resulting neonicotinoids [9] such as the open-chain compounds, e.g., nitenpyram (8), acetamiprid (9), dothianidin (12), dinotefuran (13) (Chapter 29.2.1), the five-membered ring systems, e.g., imidacloprid (7), thiacloprid (11) (Chapter 29.2.2), and the six-membered ring systems, e.g., thiamethoxam (10), AKD 1022 (14)... 

One notable omission is the five-membered thiamethoxam (10) (Chapter 29.2.3), showing binding affinities up to 10000-fofd fess than other neonicotinoids, using housefly head membrane preparations. This fow affinity may be attributed to its proneonicotinoid structure, as it was shown to be activated to the open-chain dothianidin (12) (Chapter 29.2.1) in plants and insects [135]. The latter exhibits high activity as agonist on isolated neurons at concentrations as low as 30 mM. 

Figure 29.1.3 shows the whole cell currents elicited by application of 1 xm nithiazine (6) and the commercial open-chain neonicotinoids nitenpyram (8), acetamiprid (9) and clothianidin (12). 

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). 

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]. 

To date, four open-chain type neonicotinoids have been commercialized, mainly from Japanese companies. These open-chain type neonicotinoids can have, as separate substituents, (i) (R, R ), e.g., R = hydrogen or alkyl like ethyl (1, niten-pyram) and methyl (2, acetamiprid, E-R = Me) and in the case of E = NH for the substituent R an alkyl group such as methyl (3, clothianidin and 4, dinote-furan) (Chapter 29.2, Table 29.2.1 and Eig. 29.2.1). 

AKD 1022 (18) as well as thiamethoxam (17) (Chapter 29.2.3) can form the open-chain neonicotinoid 3 by ring cleavage, either by hydrolysis (see synthesis methods in this chapter) or metabolism (Scheme 29.2.1.4). 

Generally, the open-chain neonicotinoids are less lipophilic than the corresponding neonicotinoids with a ring structure (Chapters 29.2.2 and 29.2.3). Based on CoMFA results, a binding model for imidacloprid (11) has been described. 

Fig. 29.2.1.1. Stable conformations of open-chain neonicotinoids (1,2), the five-membered ring system imidacloprid (11) and predicted properties of their binding site (Okazawa et al., 2000) [72].

On the other hand, the sterically forbidden regions beyond the imidazolidine 3-nitrogen atom of 11 is important for binding [72]. The area around the 6steric interactions were more important for open-chain neonicotinoids than ring systems. 

Finally, it was also shown that the open-chain neonicotinoids bind to the nAChR recognition site in a similar manner to ring structures like 11, and that the electrostatic properties of the open[Pg.978]

---