Docking model of the nicotinic acetylcholine receptor and nitromethylene neonicotinoid derivatives with a longer chiral substituent and their biological activities. Issue 4 (15th February 2015)

• Record Type: Journal Article
• Authors: Nagaoka, Hikaru; Nishiwaki, Hisashi; Kubo, Takuya; Akamatsu, Miki; Yamauchi, Satoshi; Shuto, Yoshihiro
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 4(2015)
• Page Start: 759
• Page End: 769
• Publication Date: 2015-02-15
• Subjects: Ac Aplysia californica -- CH-IMI nitromethylene analogue of imidacloprid -- IMI imidacloprid -- LBD ligand-binding domain -- Ls Lymnaea stagnalis -- nAChR nicotinic acetylcholine receptor -- NIA propargyl propyl phenylphosphonate (Niagara 16388) -- QSAR quantitative structure–activity relationship -- SAR structure–activity relationship; Nitromethylene neonicotinoids -- QSAR -- Docking model -- Musca domestica -- Nicotinic acetylcholine receptor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2014.12.058
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: In the present study, nitromethylene neonicotinoid derivatives possessing substituents that contain a sulfur atom, oxygen atom or aromatic ring at position 5 on the imidazolidine ring were synthesized to evaluate their affinity for the nicotinic acetylcholine receptor (nAChR) and their insecticidal activity against adult female houseflies. Comparing the receptor affinity of the alkylated derivative with the receptor affinity of compounds possessing either ether or thioether groups revealed that conversion of the carbon atom to a sulfur atom did not influence the receptor affinity, whereas conversion to an oxygen atom was disadvantageous for the receptor affinity. The receptor affinity of compounds possessing a benzyl or phenyl group was lower than that of the unsubstituted compound. Analysis of the three-dimensional quantitative structure–activity relationship using comparative molecular field analysis demonstrated that steric hindrance of the receptor should exist around the C3 of an n -butyl group attached at position 5 on the imidazolidine ring. A docking study of the nAChR–ligand model suggested that the ligand-binding region expands as the length of the substituent increases by brushing against the amino acids that form the binding region. The insecticidal activity of the compounds was positively correlated with the receptor affinity by considering log P and the number of heteroatoms, including sulfur and oxygen atoms, in the substituents, suggesting that the insecticidal activity is influenced by the receptor affinity, hydrophobicity, and metabolic stability of the compounds.