Pyrrole-2 carboxamides - A novel class of insect ryanodine receptor activators

The ryanodine receptor (RyR) is an intracellular calcium channel critical to the regulation of insect muscle contraction and the target site of diamide insecticides such as chlorantraniliprole, cyantraniliprole and flubendiamide. To-date, diamides are the only known class of synthetic molecules with high potency against insect RyRs. Target-based screening of an informer library led to discovery of a novel class of RyR activators, pyrrole-2-carboxamides. Efforts to optimize receptor activity resulted in analogs with potency comparable to that of commercial diamides when tested against RyR of the fruit fly, Drosophila melanogaster. Surprisingly, testing of pyrrole-2-carboxamides in whole-insect screens showed poor insecticidal activity, which is partially attributed to differential selectivity among insect receptors and rapid detoxification. Among various lepidopteran species field resistance to diamide insecticides has been well documented and in many cases has been attributed to a single point mutation, G4946E, of the RyR gene. As with diamide insecticides, the G4946E mutation confers greatly reduced sensitivity to pyrrole-2-carboxamides. This, coupled with findings from radioligand binding studies, indicates a shared binding domain between anthranilic diamides and pyrrole-2-carboxamides. [Display omitted] •Pyrrole-2-carboxamides are a novel RyR chemotype with sub-micromolar potency against insect receptors.•The optimized pyrrole-2-carboxamide, F-12, shares a binding site with the anthranilic diamide insecticides.•The G4946E mutation confers cross-resistance between F-12 and chlorantraniliprole.•Despite their RyR potency optimized pyrrole-2-carboxamide analogs lack insecticidal activity against key pest insects.