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