Dawn Wong - Pharmacological mapping of the acetylcholinesterase catalytic gorge in mosquitoes with bis(n)-tacrines

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  Publication Details (including relevant citation   information):

  Anderson, T. D.; Paulson, S. L.; Wong, D. M.;   Carlier, P. R.; Bloomquist, J. R. Pharmacological mapping of the   acetylcholinesterase catalytic gorge in mosquitoes with   bis(n)-tacrines.

  In Advances in Human Vector Control,   ACS Symposium Series, Clark, J. M.; Bloomquist,   J. R.; Kawada, H., Eds. American Chemical Society: Chicago, IL,   2009; Vol. 1014, Ch. 10, pp 143-151.




  New insecticides are needed for control of mosquitoes, such as   Anopheles gambiae, the major vector of malaria.   Acetylcholinesterase is a proven insecticide target site, but   conventional organophosphate and carbamate compounds are plagued   by concerns about human toxicity and resistance. A   pharmacological approach with novel, bivalent   bis(n)-tacrines was used to map the catalytic gorge of   this enzyme from human and several mosquito species   (Anopheles gambiae, Culex restuans, Aedes   aegypti, and Aedes albopictus). We screened   bivalent bis(n)-tacrines having methylene linkers from   2-12 carbons in length, where proper spacing would allow for high   potency binding via interaction with both the catalytic and   peripheral sites on the enzyme. The tacrine monomer had fairly   similar potency across species (somewhat less for Culex   restuans), indicating a common mode of binding at the   catalytic site. A greater maximal potency for a   bis(n)-tacrine was observed against human AChE than any   of the mosquitoes tested. With the exception of Anopheles   gambiae, the mosquitoes showed a clear tether length   dependence, with tether length most critical in Aedes   aegypti. This finding has implications for identifying the   targeted amino acid residues in or near the gorge. Despite the   greater potency of bis(n)-tacrines against vertebrate   than mosquito acetylcholinesterase, the information gleaned from   this study should help inform the molecular design of selective   anticholinesterase insecticides in other chemical series.

  Address (URL): http://dx.doi.org/10.1021/bk-2009-1014.ch010