Minor structural changes in nicotinoid insecticides confer differential subtype selectivity for mammalian nicotinic acetylcholine receptors

Abstract

1 The major nitroimine insecticide imidacloprid (IMI) and the nicotinic analgesics epibatidine and ABT-594 contain the 6-chloro-3-pyridinyl moiety important for high activity and/or selectivity. ABT-594 has considerable nicotinic acetylcholine receptor (AChR) subtype speci®city which might carry over to the chloropyridinyl insecticides. This study considers nine IMI analogues for selectivity in binding to immuno-isolated a 1 , a 3 and a 7 containing nicotinic AChRs and to purported a 4 b 2 nicotinic AChRs. 2 a 1 -and a 3 -Containing nicotinic AChRs (both immuno-isolated by mAb 35, from Torpedo and human neuroblastoma SH-SY5Y cells, respectively) are between two and four times more sensitive to DN-IMI than to (7)-nicotine. 3 With immuno-isolated a 3 nicotinic AChRs, the tetrahydropyrimidine analogues of IMI with imine or nitromethylene substituents are 3 ± 4 fold less active than (7)

Effects of Exposure to Clothianidin on the Reproductive System of Male Quails

“…In addition, several studies have reported that the breakdown products of neonicotinoids are toxic to mammals [4,19], and they affect the reproductive systems of male mice [22] and rats [2,12] through oxidative stress. Thus, it is suggested that neonicotinoids are harmful to mammals including human.…”

6′-Methylpyrido[3,4-b]norhomotropane: synthesis and outstanding potency in relation to the α4β2 nicotinic receptor pharmacophore model

“…18 The binding affinities of the standard nicotinoids [(À)-1, (±)-2, and (±)-3] and pyridonorhomotropanes [(±)-4 and (±)-5] were determined to both a4b2 and a7 nAChRs using (À)-[ 3 H]nicotine and [ 125 I]-a-bungarotoxin, respectively, as the radioligands (Table 1). [19][20][21] The a7 nAChR is much less sensitive than the a4b2 to all of the ligands with the highest selectivity factor for (±)-4 and (±)-5. Most importantly, the affinity of (±)-5 for the a4b2 receptor was 3-fold greater than that of (±)-4 and 36-fold greater than (±)-2, making 5 the most potent bridged nicotinoid reported for the nicotinic receptor.…”

Neonicotinoids Show Selective and Diverse Actions on Their Nicotinic Receptor Targets: Electrophysiology, Molecular Biology, and Receptor Modeling Studies

“…52) Such co-planarity, although apparently supporting neonicotinoid binding to insect nAChRs, is insufficient by itself to determine selectivity, since CH-IMI, a nitromethylene analog of imidacloprid resembling imidacloprid in both co-planarity and the electrostatic nature of the nitro group, shows high affinity for vertebrate as well as insect nAChRs. 53) The positive charge of the quaternary ammonium moiety in ACh must be overcome in binding to nAChRs. A force that has been proposed to be responsible for such compensation is the cation-interaction between a tryptophan residue in loop B with the quaternary nitrogen.…”