Neurotoxicology of bis(n)-tacrines on Blattella germanica and Drosophila melanogaster acetylcholinesterase.
Neurotoxicology of bis(n)-tacrines on Blattella germanica and Drosophila melanogaster acetylcholinesterase.
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双（n）-他克林对德国小蠊和果蝇乙酰胆碱酯酶的神经毒理学。
DOI：
10.1002/arch.21104
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发表时间：
2013
影响因子：
2.2
通讯作者：
Totrov,MaximM
中科院分区：
文献类型：
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作者：
Mutunga,JamesM;Boina,DhanaRaj;Anderson,TroyD;Bloomquist,JeffreyR;Carlier,PaulR;Wong,DawnM;Lam,PoloC-H;Totrov,MaximM
用一系列双(N)-Tacrine作为乙酰胆碱酯酶(AChE)催化和外周位点的药物探针，分别研究了表达AChE-1和AChE-2亚型的德国小蠊和黑腹果蝇。一般情况下，双(N)-三氯乙烷在黑腹果蝇(DmAChE)中的活性高于在德国乳杆菌(BgAChE)中的活性。与他克林单体相比，DmAChE的效价随系绳长度的变化较大，BgAChE的效价较低，分别是他克林单体的90倍和5.2倍。小蠊最适系绳长度为8碳，果蝇最适系绳长度为10碳。这两个物种对他克林单体的敏感性仅相差约两倍，这表明由于外围位置的结构差异，二聚体双(N)-塔克林之间出现了不同的效价。多序列比对和电子同源性建模表明，DmAChE的芳香族残基具有更高的亲和力结合，而BgAChE外围位点缺乏芳香族残基可能至少部分原因是DmAChE对二(N)-Tacrine的总体敏感性更高，如体外检测数据所反映的那样。在蟑螂身上进行的局部和注射试验发现，双(N)-塔克宁的毒性很小。对黑腹毛虫中枢神经系统的电生理学研究表明，二聚体Tacrine不容易穿过血脑屏障，这解释了观察到的对昆虫的非致命性。尽管双(N)-Tacrine不是很好的杀虫剂候选化合物，但本研究获得的信息应该有助于设计针对昆虫、害虫和疾病媒介的选择性二价配体。
A series of bis(n)‐tacrines were used as pharmacological probes of the acetylcholinesterase (AChE) catalytic and peripheral sites of Blattella germanica and Drosophila melanogaster, which express AChE‐1 and AChE‐2 isoforms, respectively. In general, the potency of bis(n)‐tacrines was greater in D. melanogaster AChE (DmAChE) than in B. germanica AChE (BgAChE). The change in potency with tether length was high in DmAChE and low in BgAChE, associated with 90‐fold and 5.2‐fold maximal potency gain, respectively, compared to the tacrine monomer. The optimal tether length for Blattella 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 DmAChE confer higher affinity binding, and the lack of same at the BgAChE peripheral site may account, at least in part, to the greater overall sensitivity of DmAChE 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.