The yellow fever mosquito, Aedes aegypti, vectors disease-causing agents that can lead to dengue and yellow fever. Current mosquito control programs are challenged by the emergence of insecticide-resistant mosquitos. One recently identified potential insecticide target is the A. aegypti D1-like dopamine receptor, AaDOP2. In this study, in vitro assays revealed AaDOP2 antagonism by four distinct chemical scaffolds from tricyclic antidepressant or antipsychotic chemical classes, and elucidated several structure-activity relationships that contributed to enhanced potency, including lipophilicity, halide substitution on the tricyclic core, and conformational rigidity. Among the compounds investigated, asenapine, methiothepin, and cis-(Z)-flupenthixol displayed subnanomolar IC50 values and caused rapid toxicity to A. aegypti larvae and/or adults in vivo. There was a significant correlation between in vitro potency for AaDOP2 antagonism and in vivo toxicity, suggesting viability of AaDOP2 as an insecticidal target.
See article at J Pharmacol Exp Ther 2015, 352:53–60.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics