title: The mode of action of a nitroconjugated neonicotinoid and the effects of target site mutation Y151S on its potency.
abstract: 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-β-erythroidine (DHβE), with pIC(50) of 6.56 ± 0.07 and 6.89 ± 0.12. The efficacy of IPPA152201 on hybrid receptors Nlα1/β2 in Xenopus oocytes and response inhibition by MLA and DHβE were also observed. These data demonstrate that IPPA152201 acts on insect nAChRs as an agonist. In addition, the influence of a Nlα1 mutation (Y151S), which has been linked to the lab-generated neonicotinoid resistance in N. lugens, has been examined. Compared to the wildtype Nlα1/β2, 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.
authors.affiliation: Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Meilong Road 130, Shanghai 200237, China.
authors.forename: Xusheng
authors.initials: X
authors.lastname: Shao
authors.forename: Haiyan
authors.initials: H
authors.lastname: Lu
authors.forename: Haibo
authors.initials: H
authors.lastname: Bao
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Xu
authors.forename: Zewen
authors.initials: Z
authors.lastname: Liu
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D003058:Cockroaches / Q000235:genetics / Q000378:metabolism; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007300:Insect Control / Q000379:methods; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism; D007305:Insecticide Resistance; D007306:Insecticides / Q000494:pharmacology*; D008564:Membrane Potentials; D009154:Mutation; D000073943:Neonicotinoids; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009574:Nitro Compounds / Q000494:pharmacology*; D009865:Oocytes / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D007093:Imidazoles; D019476:Insect Proteins; D007306:Insecticides; D000073943:Neonicotinoids; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D009574:Nitro Compounds; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; C082359:imidacloprid