Zhang Nanjing, Tomizawa Motohiro, Casida John E
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720-3112, USA.
J Med Chem. 2002 Jun 20;45(13):2832-40. doi: 10.1021/jm010508s.
The higher toxicity of neonicotinoid insecticides such as N-(6-chloropyridin-3-ylmethyl)-2-nitroiminoimidazolidine (imidacloprid) to insects than mammals is due in large part to target site specificity at the corresponding nicotinic acetylcholine receptors (nAChRs). We propose that neonicotinoids with a protonated N-unsubstituted imine or equivalent substituent recognize the anionic subsite of the mammalian alpha4beta2 nAChR whereas the negatively charged (delta(-)) tip of the neonicotinoid insecticides interacts with a putative cationic subsite of the insect nAChR. This hypothesis can be tested by using two photoaffinity probes that differ only in the N-unsubstituted imine vs negatively charged (delta(-)) tip. Synthesis methodology was developed for compounds combining three moieties: pyridin-3-ylmethyl or 6-chloropyridin-3-ylmethyl and their 4- and 5-azido analogues; imidazolidine, 4-imidazoline or 4-thiazoline; and N-unsubstituted imine, nitroimine, cyanoimine, or nitromethylene. Structure-activity studies compared displacement of [(3)H]nicotine binding in mammalian alpha4beta2 nAChR and [(3)H]imidacloprid binding in Drosophila nAChR. Preferred compounds are N-(5-azido-6-chloropyridin-3-ylmethyl) with 2-iminothiazoline for alpha4beta2 (K(i) = 0.47 nM) and with 2-nitroiminothiazoline or 2-nitromethyleneimidazolidine for Drosophila (K(i) = 0.72-3.9 nM).
与哺乳动物相比，新烟碱类杀虫剂如N-(6-氯吡啶-3-基甲基)-2-硝基亚氨基咪唑烷（吡虫啉）对昆虫的毒性更高，这在很大程度上归因于其对相应烟碱型乙酰胆碱受体（nAChRs）的靶位点特异性。我们提出，具有质子化N-未取代亚胺或等效取代基的新烟碱类化合物识别哺乳动物α4β2 nAChR的阴离子亚位点，而新烟碱类杀虫剂带负电荷（δ-）的末端与昆虫nAChR的一个假定阳离子亚位点相互作用。这一假设可以通过使用两种仅在N-未取代亚胺与带负电荷（δ-）末端不同的光亲和探针来进行验证。开发了用于合成结合三个部分的化合物的方法：吡啶-3-基甲基或6-氯吡啶-3-基甲基及其4-和5-叠氮类似物；咪唑烷、4-咪唑啉或4-噻唑啉；以及N-未取代亚胺、硝基亚胺、氰基亚胺或硝基亚甲基。构效关系研究比较了[(3)H]尼古丁在哺乳动物α4β2 nAChR中的结合取代情况以及[(3)H]吡虫啉在果蝇nAChR中的结合取代情况。优选的化合物是对于α4β2而言，带有2-亚氨基噻唑啉的N-(5-叠氮-6-氯吡啶-3-基甲基)（K(i)=0.47 nM），以及对于果蝇而言，带有2-硝基亚氨基噻唑啉或2-硝基亚甲基咪唑烷的N-(5-叠氮-6-氯吡啶-3-基甲基)（K(i)=0.72 - 3.9 nM）。
