Targeting the GABA receptor for agricultural Pest control: from molecular mechanisms to novel NAM site inhibitors

The ionotropic γ-aminobutyric acid receptor (GABAR) is a major inhibitory neurotransmitter receptor in the insect central nervous system and a proven target for multiple classes of insecticides. The recent discovery of the NAM binding site located at the transmembrane subunit interface has revitalized interest in this classic target, leading to the development of two novel classes of insecticides-isoxazolines and meta-diamides-that offer potent efficacy and lack cross-resistance with conventional agents. This review provides a comprehensive overview of the molecular basis of insect GABARs, including subunit composition, gating mechanisms, and the structural pharmacology of distinct binding sites, with an emphasis on the NAM site. We highlight key advances in understanding the mode of action, resistance mechanisms, and structure-activity relationships of NAM inhibitors, and critically evaluate their future potential. A central challenge for this class of insecticides remains their generally high toxicity to honeybee pollinators, which we argue is an inherent consequence of the high sequence conservation of the RDL subunit between pests and beneficial insects. Strategies for mitigating bee toxicity while retaining insecticidal potency are discussed. © 2026 Society of Chemical Industry.