Selectivity neonicotinoids

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. 

Yu and Nguyen (1996) showed that selection of a strain of diamondback moth (Plu-tella xylostella) with permethrin for 21 generations resulted in over 600-fold resistance to permethrin in this strain. The resistant strain was also cross-resistant to all pyrethroids tested, including bifenthrin, fenvalerate, esfenvalerate, A.-cyhalothrin, fluvalinate, and tral-omethrin. However, it remained susceptible to organophosphate, carbamate, cyclodiene, neonicotinoid, avermectin, and microbial insecticides tested. Biochemical studies indicated that pyrethroid resistance observed in this strain was most likely due to decreased target site sensitivity. 

Tomizawa M and Casida JE (2003) Selective toxicity of neonicotinoids attributable to specificity of insect and mammalian nicotinic receptors. Annual Reviews in Entomology 48 339-364. 

Nithiazine (Figure 2) was the first neonicotinoid developed by Shell (Modesto, USA) in the 1970s. Nithiazine is a 2-nitromethylene tetrahydro-1, 3-thiazine selected from a series of nitroalkyl heterocyclic compounds, the molecular models being distinct from nicotine but acting on the nicotinic... 

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... 

Nithiazine has historical importance as a compound on which neonicotinoids, a new class of insecticides, have been modeled. Its synthesis was accomplished by Shell (Modesto, CA) in the 1970s based on selection from a series of nitroalkyl heterocyclic compounds. 

Yamamoto, L, Yabuta, G., Tomizawa, M., Saito, T., Miyamoto, T., and Kagabu, S. 1995. Molecular mechanism for selective toxicity of nicotinoids and neonicotinoids. 

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. 

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

Computational model. Based on the bioinformatic analysis and the known mutation data [8-10] of insect nAChR, two key residues (Arg and Trp) were selected to build a computational model with three analogs of neonicotinoids. Considering the computational efficiency, the structures were simplified as seen in Figure 1. 

Exploring Structural Features of nAChRs Contributing to the Selectivity of Neonicotinoids 1263... 

Homology Modeling of nAChRs has Assisted in the Identification of Key Amino Acid Residues Involved in the Selective Interactions with Neonicotinoids of Heteromeric Nicotinic Acetylcholine Receptors... 

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