Structural features of azidopyridinyl neonicotinoid probes conferring high affinity and selectivity for mammalian alpha4beta2 and Drosophila nicotinic receptors.
Structural features of azidopyridinyl neonicotinoid probes conferring high affinity and selectivity for mammalian alpha4beta2 and Drosophila nicotinic receptors.
复制标题
叠氮吡啶基新烟碱探针的结构特征赋予哺乳动物 α4β2 和果蝇烟碱受体高亲和力和选择性。
DOI：
10.1021/jm010508s
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发表时间：
2002
影响因子：
7.3
通讯作者：
Casida,JohnE
中科院分区：
文献类型：
--
作者：
Zhang,Nanjing;Tomizawa,Motohiro;Casida,JohnE
The higher toxicity of neonicotinoid insecticides such asN-(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 protonatedN-unsubstituted imine or equivalent substituent recognize the anionic subsite of the mammalian α4β2 nAChR whereas the negatively charged (δ-) 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 theN-unsubstituted imine vs negatively charged (δ-) 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; andN-unsubstituted imine, nitroimine, cyanoimine, or nitromethylene. Structure−activity studies compared displacement of [3H]nicotine binding in mammalian α4β2 nAChR and [3H]imidacloprid binding inDrosophilanAChR. Preferred compounds areN-(5-azido-6-chloropyridin-3-ylmethyl) with 2-iminothiazoline for α4β2 (Ki= 0.47 nM) and with 2-nitroiminothiazoline or 2-nitromethyleneimidazolidine forDrosophila(Ki= 0.72−3.9 nM).
