Evaluation of AaDOP2 receptor antagonists reveals antidepressants and antipsychotics as novel lead molecules for control of the yellow fever mosquito, Aedes aegypti

The yellow fever mosquito, Aedes aegypti , vectors disease-causing agents that adversely affect human health, most notably the viruses causing dengue and yellow fever. The efficacy of current mosquito control programs is challenged by the emergence of insecticide-resistant mosquito populations, suggesting an urgent need for the development of chemical insecticides with new mechanisms of action. One recently identified potential insecticide target is the A. aegypti D 1 -like dopamine receptor, Aa DOP2. The focus of the present study was to evaluate Aa DOP2 antagonism both in vitro and in vivo using assay technologies with increased throughput. The in vitro assays revealed Aa DOP2 antagonism by four distinct chemical scaffolds from tricyclic antidepressant or antipsychotic chemical classes, and elucidated several structure-activity relationship trends that contributed to enhanced antagonist potency, including lipophilicity, halide substitution on the tricyclic core, and conformational rigidity. Six compounds displayed previously unparalleled potency for in vitro Aa DOP2 antagonism, and among these, asenapine, methiothepin, and cis -( Z )-flupenthixol displayed subnanomolar IC 50 values and caused rapid toxicity to A. aegypti larvae and/or adults in vivo. Our study revealed a significant correlation between in vitro potency for Aa DOP2 antagonism and in vivo toxicity, suggesting viability of Aa DOP2 as an insecticidal target. Taken together, this study expanded the repertoire of known Aa DOP2 antagonists, enhanced our understanding of Aa DOP2 pharmacology, provided further support for rational targeting of Aa DOP2, and demonstrated the utility of efficiency-enhancing in vitro and in vivo assay technologies within our genome-to-lead pipeline for the discovery of next-generation insecticides.