Dawn Wong - Inhibition of Blatella germanica acetylcholinesterase by bis(n)-tacrines:  Prospects for the molecular design of a selective insecticide for a household pest

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      Publication Details (including relevant citation   information):

      Mutunga, J. M.; Anderson, T. D.; Wong, D. M.;   Carlier, P. R.; Bloomquist, J. R. Inhibition of Blatella   germanica acetylcholinesterase by bis(n)-tacrines:   Prospects for the molecular design of a selective insecticide for   a household pest.

      In Pesticides in Household, Structural and   Residential Pest Management, ACS Symposium   Series, Peterson, C. J.; Stout II, D. M., Eds. American   Chemical Society: Chicago, IL, 2009; Vol. 1015, Ch. 4, pp 41-51   (book printed in 2010).




      The German cockroach (Blattella germanica, L.) is a   major household pest that has developed resistance to most   insecticides on the market. There is a need to develop   insecticides that are less likely to induce resistance, are   potent against insect pests including resistant populations, and   possess less toxicity to humans. In this study,   9-amino-1,2,3,4-tetrahydroacridine (tacrine) was chosen as the   acetylcholinesterase (AChE) inhibitor pharmacophore. We screened   bivalent bis(n)-tacrines having methylene linkers from   2-12 carbons in length and determined their activity on   BgAChE, to probe the geometry of the AChE active site   gorge. The dimeric tacrine having an octylene linker   [bis(8)-tacrine] was the most potent analog against   BgAChE (IC50= 68 nM). Some binding   interference was observed with a 2-methylene linker   ("C2 bump") and with a 12-methylene linker   ("C12 bump"), associated with a 4-fold and 7-fold loss   in potency, respectively. It is possible that such “bumps” might   convey underlying structural preferences of AChE in general, or   of a particular species of AChE; further screening is on-going to   test this hypothesis. Moreover, the most significant finding is   that tether length dependent inhibition potency of   bis(n)-tacrines relative to tacrine seems to differ   across organisms, with the BgAChE being both less   sensitive overall, and less dependent on compound length compared   to rat AChE. Such differences provide opportunities for   comparative molecular modeling, and may inspire the synthesis of   compounds that are specific and selective to insects.

      Address (URL): http://dx.doi.org/10.1021/bk-2009-1015.ch004