Interaction of dinotefuran and its analogues with nicotinic acetylcholine receptors of cockroach nerve cords

Abstract

To investigate the action of dinotefuran (MTI-446, 1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine), a recently developed insecticide, on insect nicotinic acetylcholine receptors (nAChRs), we determined the potencies of the compound and 15 analogues in inhibiting the specific binding of [3H]epibatidine (EPI), a nAChR agonist, and [3H]alpha-bungarotoxin (alpha-BGT), a competitive nAChR antagonist, to the nerve cord membranes of American cockroaches (Periplaneta americana). Racemic dinotefuran inhibited [3H]EPI binding with an IC50 of 890 nM and [3H]alpha-BGT binding with an IC50 of 36.1 microM. Scatchard analysis indicated that the dinotefuran inhibition of [3H]EPI binding was a competitive one. Slight structural modification caused a drastic reduction in potency; only four analogues were found to be equipotent to or more potent than dinotefuran. Chloropyridinyl and chlorothiazolyl neonicotinoid insecticides displayed two or three orders of magnitude higher potency than dinotefuran. There was a good correlation between the IC50 values of tested compounds obtained with [3H]EPI and those obtained with [3H]alpha-BGT. A better correlation was observed between 3-h knockdown activities (KD50) against German cockroaches (Blattella germanica) and IC50 values obtained from [3H]EPI assays than between 24-h lethal activities (LD50) and IC50 values. While the results indicate that dinotefuran and its analogues interact with the ACh-binding site in cockroach nAChRs, it remains to be elucidated why they displayed lower potencies than those expected based on their insecticidal activities.

Synthesis and Structure-Activity Relationships of Dinotefuran Derivatives: Modification in the Nitroguanidine Part

“…Both derivatives have the same clear trend for decreased activity with increasing size of the N-alkyl substituents. The mono-methyl compounds (15) and (5), which showed the highest levels of activity among these compounds, had the same activity level. Removal of the methyl substituent on the guanidine of 15 strongly reduced the activity (see 14).…”

“…The acyclic nitroimino compounds (14)(15)(16)(17)(18)(19)(20)(21)(22) and the acyclic nitromethylene compounds (5-13) are similar in SAR and activity level. Both derivatives have the same clear trend for decreased activity with increasing size of the N-alkyl substituents.…”

“…[5][6][7][8] In this research, hundreds of related compounds were synthesized and the SARs for two moieties were obtained. Since publication of our research on dinotefuran, much related research has been reported, but many of the studies were about residue analysis, 9,10) metabolism [11][12][13] and mode of action, [14][15][16] and there are not enough reports about the SAR of dinotefuran. 5,15,17) In this paper we describe the preparation of four types of (Ϯ)-tetrahydro-3-furylmethy derivatives and the SAR for the nitroguanidine part of dinotefuran.…”

Design, synthesis, and insecticidal activity of novel neonicotinoid derivatives containing N-oxalyl groups

“…Neonicotinoids, which interact with nicotinic acetylcholine receptors (nAChR), have a higher affinity for the insect receptor than for the mammalian receptor and are relatively safe toward mammals and aquatic life. [2][3][4][5] Imidacloprid (1), the first neonicotinoid insecticide acting on a nAChR, has been widely used to control not only various plant pests, but also fleas on cats and dogs, and termites. [6][7][8] Following imidacloprid, thiamethoxam (2), thiacloprid (3), acyclic neonicotinoid insecticides, dinotefuran (4), acetamiprid (5), nitenpyram (6), and clothianidin (7) have been registered as agricultural insecticides.…”

Synthesis and insecticidal activity of N-cyano 2-(substituted amino) ethyl methyl sulfoximine derivatives

“…[2][3][4][5][6][7][8] Neonicotinoid insecticides were used rapidly worldwide for controlling insects because of their high potency, low mammalian toxicity, broad insecticidal spectra, and good systemic properties. Neonicotinoids interacting with nicotinic acetylcholine receptors (nAChR) have a higher affinity for the insect receptor than for the mammalian [9][10][11][12] and are relatively safe toward mammals and aquatic life.…”