- Azido-neonicotinoids as candidate photoaffinity probes for insect nicotinic acetylcholine receptors [1]
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The neonicotinoids are the most successful chemical class of insecticides reaching sales of more than 630 Mio $ in 2001, mainly due to the excellent market performance of imidacloprid and thiamethoxam. The insect nicotinic acetylcholine receptors (nAChRs) are the targets for these compounds, which are highly effective against a variety of sucking and chewing insects. Compared with the other neonicotinoid sales products, thiamethoxam binds in a different way, possibly to a different site of nAChRs in aphids. To gain further insight into the different modes of binding, a research program applying the photoaffinity labeling technique was started. A series of novel candidate photoaffinity probes containing a 5-azido-6-chloropyridin-3-ylmethyl group were prepared from 5-azido-6-chloropyridin-3-ylmethyl chloride, which was obtained in three steps from 6-chloropyridin-3-ylmethyl chloride. These probes showed good to excellent contact/feeding and systemic activity against Myzus persicae, however, they were at least 4- to 16-fold less effective against Aphis craccivora, Nilaparvata lugens, Spodoptera littoralis, and Diabrotica balteata than the neonicotinoid sales products. In general, the introduction of an azide group at C(5) of the 6-chloropyridin-3-ylmethyl substituent resulted in reduced potency as well as in a narrower pest spectrum. In competition binding assays with [3H]imidacloprid, analogues of imidacloprid, clothianidin, thiacloprid and thiamethoxam containing a 5-azido-6-chloropyridin- 3-ylmethyl group showed high displacing potency with nAChRs from Aphis and Myzus (Ki values: 2 to 27 nM) suggesting that these compounds are valuable candidate photoaffinity probes. Taking into account the biological screening activity as well as the receptor binding potency, 1-(5-azido-6- chloropyridin-3-ylmethyl)-2-nitroimino-imidazolidine N-(5-azido-6-chloropyridin- 3-ylmethyl)-N′-methyl-N″-nitroguanidine and 3-(5-azido-6- chloropyridin-3-ylmethyl)-2-cyanoimino-thiazolidine were identified as the preferred candidate neonicotinoid photoaffinity probes to study the imidacloprid binding site.
- Maienfisch, Peter,Haettenschwiler, Joerg,Rindlisbacher, Alfred,Decock, Arnaud,Wellmann, Henning,Kayser, Hartmut
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p. 710 - 714
(2007/10/03)
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- Structural features of azidopyridinyl neonicotinoid probes conferring high affinity and selectivity for mammalian α4β2 and Drosophila nicotinic receptors
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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 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 the N-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; and N-unsubstituted imine, nitroimine, cyanoimine, or nitromethylene. Structure-activity studies compared displacement of [3H] nicotine binding in mammalian α4β2 nAChR and [3H]imidacloprid binding in Drosophila nAChR. Preferred compounds are N-(5-azido-6-chloropyridin-3-ylmethyl) with 2-iminothiazoline for α4β2 (Ki = 0.47 nM) and with 2-nitroiminothiazoline or 2-nitromethyleneimidazolidine for Drosophila (Ki = 0.72-3.9 nM).
- Zhang, Nanjing,Tomizawa, Motohiro,Casida, John E.
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p. 2832 - 2840
(2007/10/03)
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- 5-Azidoimidacloprid and an acyclic analogue as candidate photoaffinity probes for mammalian and insect nicotinic acetylcholine receptors
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The 5-azido analogue of the major insecticide imidacloprid, 1-(5-azido-6-chloropyridin-3-ylmethyl)-2-nitroiminoimidazolidine (1), and an acyclic analogue, N-(5-azido-6-chloropyridin-3-ylmethyl)-N′-methyl-N″′-nitrog uanidine (2), were prepared in good yields as candidate photoaffinity probes for mammalian and insect nicotinic acetylcholine receptors (nAChRs). The essential intermediate was 5-azido-6-chloropyridin-3-ylmethyl chloride (3) prepared in two ways: from 6-chloro-5-nitronicotinic acid by selective reduction and then diazotization, and from N-(6-chloropyridin-3-ylmethyl)morpholine by an electrophilic azide introduction with lithium diisopropylamide followed by chlorine substitution of morpholine with ethyl chloroformate. Coupling of 3 with 2-nitroiminoimidazolidine gave 1. Conversion of 3 to 2 was achieved in good yields via the hexahydrotriazine intermediate 14. Fortuitously, the azido substituent in 1 and 2 increases the affinity 7-79-fold for rat brain and recombinant α4β2 nAChRs (Kis 4.4-60 nM competing with [3H](-)-nicotine) while maintaining high potency on both insect nAChRs (Drosophila and Myzus) (Kis 1-15 nM competing with [3H]imidacloprid). Azidopyridinyl compounds 1 and 2 are therefore candidate photoaffinity probes for characterization of both mammalian and insect receptors.
- Kagabu,Maienfisch,Zhang,Granda-Minones,Haettenschwiler,Kayser,Maetzke,Casida
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p. 5003 - 5009
(2007/10/03)
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