+ Site Statistics
+ Resolve Accession
+ Subscribe to Site Feeds
EurekaMag Most Shared ContentMost Shared
EurekaMag PDF Full Text ContentPDF Full Text
+ PDF Full Text
Request PDF Full TextRequest PDF Full Text
Submit PDF Full TextSubmit PDF Full Text
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter
Follow on Google+Follow on Google+
Follow on LinkedInFollow on LinkedIn

+ Translate

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

, : Evaluation of AaDOP2 receptor antagonists reveals antidepressants and antipsychotics as novel lead molecules for control of the yellow fever mosquito, Aedes aegypti. Journal of Pharmacology and Experimental Therapeutics 352(1): 53-60

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 D1-like dopamine receptor, AaDOP2. The focus of the present study was to evaluate AaDOP2 antagonism both in vitro and in vivo using assay technologies with increased throughput. The in vitro assays revealed AaDOP2 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 AaDOP2 antagonism, and among these, asenapine, methiothepin, and cis-(Z)-flupenthixol displayed subnanomolar IC50 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 AaDOP2 antagonism and in vivo toxicity, suggesting viability of AaDOP2 as an insecticidal target. Taken together, this study expanded the repertoire of known AaDOP2 antagonists, enhanced our understanding of AaDOP2 pharmacology, provided further support for rational targeting of AaDOP2, 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.

(PDF same-day service: $19.90)

Order PDF Full Text


Click here to order any other PDF Full Text

Accession: 053060450

PMID: 25332454

DOI: 10.1124/jpet.114.219717

PDF Full Text: Submit

Submit PDF Full Text

No spam - Every submission is manually reviewed

Due to poor quality, we do not accept files from Researchgate

Submitted PDF Full Texts will always be free for everyone
(We only charge for PDFs that we need to acquire)

Select a PDF file:

Other references

Grigorev D. P. (Grigoriev); Lebedeva O. N. Lebedeva, 1941: On the products of fusing hornblende with fluoride additions. Hornblende was fused with ammonium fluoride and the melt allowed to crystallize. The result, uncomplicated by the introduction of foreign metallic elements, was especially interesting because mica crystallized before hornblende, contrary to Bowen&...

Gusel'nikov, V. I.; Onufrieva, M. I.; Supin, A. Ya, 1964: Representation of the visual, olfactory, and lateral-line receptors in the fish brain. Experiments on goldfish demonstrate that evokedpotentials reveal demarcated representation of the olfactory analyzer in the forebrain of fish, the visual analyzer in the visual tegmina of the midbrain, and the lateral-line analyzer in the cerebell...

Schwalbe G.P.; Schwalbe P.W., 1975: Corn stubble soybeans and hay field. American Birds 29(3): 784

Farhoudi, A.; Hashemian, H.; Sepehrzad, T.; Dayhimi, I., 1995: Immunogenetic studies in common variable immunodeficiencies including IgA deficiency disorder. Journal of Allergy & Clinical Immunology 95(1 PART 2): 236

Heninger R.W.; Marcusen D.C., 1976: Effect of ascorbic acid on thyroid function in rats. Federation Proceedings 35(3): 216

Pflanz, S.; Kurth, I.; Grötzinger, J.; Heinrich, P.C.; Müller-Newen, G., 2000: Two different epitopes of the signal transducer gp130 sequentially cooperate on IL-6-induced receptor activation. Cytokines are key mediators for the regulation of hemopoiesis and the coordination of immune responses. They exert their various functions through activation of specific cell surface receptors, thereby initiating intracellular signal transduction...

Eap C.B.; Baumann P.; Moretta A., 1989: Synthesis of alpha 1 acid glycoprotein by human t lymphocytes. Experientia (Basel) 45(ABSTR): A52

Rodhe Wilhelm, 1975: President's lecture; the SIL founders and our fundament. Verhandlungen - Internationale Vereinigung fuer Theoretische und Angewandte Limnologie = Proceedings - International Association of Theoretical and Applied Limnology 19(Part 1): 16-25

Evenchick C. A.; Thorkelson D. J., 2005: Structural cross-sections of north and northwest Spatsizi River map area. Bulletin - Geological Survey of Canada Pages

Saxena S.K.; Singh J.P., 1982: A rare echinostome parasite ruffetrema indirae new genus new species trematoda echinostomatidae from a fresh water indian dolphin platanista gangetica. An echinostome parasite belonging to a new genus was described [RUFFETRENA indirae ] from a freshwater Indian dolphin (P. gangetica). It has a ruff-like projecting collar around the cervical region and the collar is deeply notched mid-ventrally. I...