反抗性新煙堿殺蟲劑的開發(fā)

徐曉勇

摘 要：作用于煙堿型乙酰膽堿受體（nAChRs）的新煙堿類殺蟲劑自問世以來由于其活性高，殺蟲譜廣，對(duì)哺乳動(dòng)物和水生動(dòng)物毒性低，且有良好的內(nèi)吸性及適當(dāng)?shù)奶镩g穩(wěn)定性而成為農(nóng)藥創(chuàng)制的重要熱點(diǎn)領(lǐng)域。隨著新煙堿類殺蟲劑品種的大量頻繁使用，已經(jīng)產(chǎn)生了嚴(yán)重抗性，2005年稻飛虱對(duì)吡蟲啉的抗性高達(dá)400倍以上，此外，由于頻繁持續(xù)的使用，也對(duì)環(huán)境產(chǎn)生一定的負(fù)面影響，如，在歐洲和日本都相繼發(fā)現(xiàn)吡蟲啉對(duì)蜜蜂種群的影響，最高減少40%的蜜蜂數(shù)量，嚴(yán)重影響了作物花粉的傳播。因此，從新的作用模型出發(fā)，針對(duì)業(yè)已出現(xiàn)的抗性問題和蜜蜂毒性，以提高生物選擇性為切入點(diǎn)，開展靶向性的分子設(shè)計(jì)與合成，這對(duì)我國具有自主知識(shí)產(chǎn)權(quán)的新農(nóng)藥創(chuàng)制和農(nóng)業(yè)害蟲防治都具有重要意義。主要研究內(nèi)容：（1）系統(tǒng)研究稻飛虱、煙粉虱等重大農(nóng)業(yè)害蟲對(duì)吡蟲啉等新煙堿殺蟲劑的抗性機(jī)制和基于分子靶標(biāo)的作用模型；（2）以超高活性的順硝烯化合物為基礎(chǔ)，研究高活性的先導(dǎo)化合物生物合理性分子設(shè)計(jì)、先導(dǎo)結(jié)構(gòu)多樣性衍生與優(yōu)化，創(chuàng)制順硝烯反抗性新煙堿殺蟲劑；（3）研究基于抗性機(jī)制的分子生物學(xué)和分子毒理學(xué)，建立與完善基于分子靶標(biāo)的反抗性殺蟲劑創(chuàng)制體系。預(yù)期目標(biāo)：通過超高活性的先導(dǎo)化合物生物合理性分子設(shè)計(jì)、先導(dǎo)結(jié)構(gòu)多樣性衍生與優(yōu)化研究，強(qiáng)化我國在順硝烯反抗性新煙堿殺蟲劑創(chuàng)制領(lǐng)域的優(yōu)勢(shì)。在活性化合物的基礎(chǔ)上，開展基于抗性機(jī)制的分子生物學(xué)和分子毒理學(xué)研究，建立與完善基于分子靶標(biāo)的反抗性機(jī)制殺蟲劑創(chuàng)制體系。申請(qǐng)國際PCT專利，并進(jìn)入指定國，進(jìn)行高活性化合物的中試工藝研究，完成擴(kuò)大殺蟲譜試驗(yàn)和小區(qū)試驗(yàn)測試高活性化合物的急性經(jīng)皮、經(jīng)口、急性吸入、Ames試驗(yàn)、蜜蜂毒性等數(shù)據(jù)，為申請(qǐng)農(nóng)藥登記證做好前期工作。

關(guān)鍵詞：反抗性 新煙堿 順式構(gòu)型

Abstract：Neonicotinoids acting on nAChRs have become the important hot-point research area because of its high bioactivities， broad spectrum， low toxicity to mammal and aquatic organisms， good systemic and suitable stability since they came into the market. With the using of large amount of neonicotinoids， the resistance is becoming very serious. The resistance ratio to imidacloprid aganist brown planthopper reached to 400 folds in 2005. In addition， frequent and continuous use result in negitive effect to the environment， for example， it was found in succession that imidacloprid influented the bee populations in Europe and Japan， the amount of bee decrease 40%， which affected seriously the spead of crop plllen. Therefore， based no the new model of action， targeting on the emerging resistance and bee toxicity， to improve the biological selectivity as the breakthrough point， we begin to target-orientation molecular design and synthesis， which is significant for the research and development of new pesiticde with independent intellectual property rights and the agricultural pest control. Main research content：（1）systemic research the resisitance mechanism and the model of action based on the molecular target of imidacloprid to planthopper and besimia tabaci etc. important agricultural pests；（2）Study the biological rational design of leading compounds with high activities， derivative and modification of lead structures based on the super high bioactivity of cis-configuration nitro methelene compounds and develop cis-configuration anti-resictance insecticide；（3）Study the molecular biology and toxicology based on the resistance mechanism and build and improve the research and development system of anti-resistance insecticides. Target： Through the study on the biological rational design of leading compounds with super high activities， derivative and modification of lead structures， the advantage of cis-configuration nitro methelene anti-resictance insecticide in our country is strengthened further. Based on the strucuture of the compound with activities， the researches on the molecular biology and toxicology based on the resistance mechanism are carried out and build and improve the research and development system of anti-resistance insecticides. To apply the PCT patent and come into the foreign countries， study the pilot process of the compound with hign activities， finish the experiments on broad spectrum and field trial， detemination the data of acute Acute percutaneous， acute through the mouth， acute inhalation， Ames test， bee toxicity， prepare the early stage work for the application of pesticide registration certificate.

Key Words：Anti-resistance；Neonicotinoids；Cis-configuration

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