The mode of action of a nitroconjugated neonicotinoid and the effects of target site mutation Y1515 on its potency

Neonicotinoid insecticides, such as imidacloprid, are selective agonists of the insect nicotinic acetylcholine receptors (nAChRs) with -NO(2) or -CN group in trans-configuration. Previously we reported the excellent insecticidal activity of a series of nitroconjugated neonicotinoids with -NO(2) or -CN group in cis-configuration by replacing nitromethylene pharmacophore with a nitroconjugated system. To understand the action mode of these nitroconjugated neonicotinoids, a representative member IPPA152201 was chosen to perform toxicity and pharmacology studies. IPPA152201 showed a comparable toxicity with imidacloprid against Nilaparvata lugens in a susceptible strain and had no significant cross-resistance in an imidacloprid resistant strain. IPPA152201 showed good efficacies on the isolated cockroach neurons (pEC(50) = 5.91 +/- 0.14) and the evoked responses by IPPA152201 could be blocked by the typical nAChRs antagonists methyllycaconitine citrate (MLA) and dihydro-beta-erythroidine (DH beta E), with pIC(50) of 6.56 +/- 0.07 and 6.89 +/- 0.12. The efficacy of IPPA152201 on hybrid receptors NI alpha 1/beta 2 in Xenopus oocytes and response inhibition by MLA and DH beta E were also observed. These data demonstrate that IPPA152201 acts on insect nAChRs as an agonist. In addition, the influence of a NI alpha 1 mutation (Y151S), which has been linked to the lab-generated neonicotinoid resistance in N. lugens, has been examined. Compared to the wildtype NI alpha 1/beta 2, this mutation reduced I(max) for IPPA152201 to 63.2% and caused a 1.5-fold increase in EC(50), which is much smaller than the effects on imidacloprid. The high insecticidal activity and little influence by Y151S mutation make IPPA152201 to be a potential insecticide to manage N. lugens. (C) 2011 Elsevier Ltd. All rights reserved.