Azobenzene‐isoxazoline as photopharmacological ligand for optical control of insect GABA receptor and behavior

BACKGROUND Photopharmacology is a fast‐growing photonics‐based technology, which realizes the high‐resolution regulation of drugs in time and space through light. The purpose of this research was to introduce photochromic groups into the isoxazoline structure to realize the regulation of γ‐Aminobutyric acid receptors (GABARs) targeting insect behavior. RESULTS Azobenzene‐Fluralaner analogs ABF02, ABF03 and ABF04 have been proven to have larvicidal activity against mosquito larvae. Cis‐ABF03 had excellent larvicidal activity against mosquito larvae with a median lethal concentration (LC50) value of 1.63, which was better than that of trans‐ABF03 (LC50 = 3.90). In particular, ABF03 also showed insecticidal activity against Mythimna separata. Further experiments showed that ABF03 (1 μm) induced depolarization of dorsal unpaired median neurons after ultraviolet light irradiation, enhanced affinity to the receptor, and blocked ligand‐gated chloride channels of GABARs. ABF03 (1 μm) realized the real‐time photoregulation of the behavior of mosquito larvae, which indicated that the synthesized ligand can complete the binding and off‐target action of drugs and targets in vivo under the regulation of light. CONCLUSION Azobenzene‐Isoxazoline as photopharmacological ligand was synthesized and evaluated for optical control of insect GABARs and behavior for the first time. ABF03 completed the differential regulation of cockroach neurons and the real‐time reversible regulation of insect behavior. The establishment of photochromic ligands provides a new strategy for basic and convenience‐oriented research on GABARs in invertebrates. © 2021 Society of Chemical Industry. Photochromic ligands changed between trans and cis isomeric forms during the cycle from ultraviolet light to blue light and successfully achieved the real‐time photoregulation of living insects.