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NEUROTOXICOLOGY OF bis ( n )‐TACRINES ON Blattella germanica AND Drosophila melanogaster ACETYLCHOLINESTERASE
Author(s) -
Mutunga James M.,
Boina Dhana Raj,
Anderson Troy D.,
Bloomquist Jeffrey R.,
Carlier Paul R.,
Wong Dawn M.,
Lam Polo C.H.,
Totrov Maxim. M.
Publication year - 2013
Publication title -
archives of insect biochemistry and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.576
H-Index - 66
eISSN - 1520-6327
pISSN - 0739-4462
DOI - 10.1002/arch.21104
Subject(s) - acetylcholinesterase , potency , drosophila melanogaster , tacrine , aché , biology , homology modeling , biochemistry , melanogaster , stereochemistry , pharmacology , in vitro , enzyme , chemistry , gene
A series of bis(n)‐tacrines were used as pharmacological probes of the acetylcholinesterase ( AC h E ) catalytic and peripheral sites of B lattella germanica and D rosophila melanogaster, which express AC h E ‐1 and AC h E ‐2 isoforms, respectively. In general, the potency of bis(n)‐tacrines was greater in D . melanogaster AC h E ( D m AC h E ) than in B . germanica AC h E (BgAChE). The change in potency with tether length was high in D m AC h E and low in B g AC h E , associated with 90‐fold and 5.2‐fold maximal potency gain, respectively, compared to the tacrine monomer. The optimal tether length for B lattella was 8 carbons and for Drosophila was 10 carbons. The two species differed by only about twofold in their sensitivity to tacrine monomer, indicating that differential potency occurred among dimeric bis(n)‐tacrines due to structural differences in the peripheral site. Multiple sequence alignment and in silico homology modeling suggest that aromatic residues of D m AC h E confer higher affinity binding, and the lack of same at the B g AC h E peripheral site may account, at least in part, to the greater overall sensitivity of D m AC h E to bis(n)‐tacrines, as reflected by in vitro assay data. Topical and injection assays in cockroaches found minimal toxicity of bis(n)‐tacrines. Electrophysiological studies on D . melanogaster central nervous system showed that dimeric tacrines do not readily cross the blood brain barrier, explaining the observed nonlethality to insects. Although the bis(n)‐tacrines were not good insecticide candidates, the information obtained in this study should aid in the design of selective bivalent ligands targeting insect, pests, and disease vectors.