新烟碱类杀虫剂及稠环固定的顺式衍生物研究进展

新烟碱类杀虫剂是第四大类重要的杀虫剂,主要作用于昆虫的烟碱乙酰胆碱受体(nAChRs)。概述分析了新烟碱类杀虫剂的结构特征、作用机制及其构型,综述了近5年来新烟碱类杀虫剂的研究进展,并在比较分析的基础上,阶段性总结了作者近年来在稠环固定的顺式衍生物方面的研究工作。     

新烟碱类杀虫剂选择作用的分子机理

新烟碱类是一类重要的新颖杀虫剂,其发现是近20年来杀虫剂研究的一个里程碑。烟碱类和新烟碱类杀虫剂虽然都是作为后突触烟碱乙酰胆碱受体(nAChRs)的激动剂作用于昆虫的神经系统,但由于作用方式不同,新烟碱类杀虫剂对昆虫表现出选择性毒性。根据烟碱类和新烟碱类杀虫剂结构与活性的关系、分子特性以及它们与nAChR的结合部位和亚部位的选择性阐释了新烟碱类杀虫剂选择作用的分子机理。     

烟碱乙酰胆碱受体及其与新烟碱类相互作用的研究进展

对烟碱乙酰胆碱受体(nAChRs)的结构与功能、配体结合部位、门控机理以及与新烟碱类的相互作用进行了综述,并对nAChRs亚基基因突变和敲除对新烟碱类和多杀菌素敏感性的影响进行了讨论。nAChRs在脊椎动物和昆虫的胆碱能突触的快速神经传递中起着重要作用,其在昆虫中仅存在于中枢神经系统(CNS)中,而在脊椎动物中同时存在于CNS和神经肌肉连接处。nAChRs是新烟碱类杀虫剂、多杀菌素和杀螟丹的作用靶标。肌肉和CNS中的nAChRs是一个由两个α和三个非α(β,γ和δ)亚基组成的异数五聚体,该受体主要有三部分:一个在细胞外发现的区域(胞外区)、一个位于膜内的区域(跨膜区),另一个是位于细胞内的区域(胞质区)。每个亚基(从N-C端)都具有一个包含乙酰胆碱(ACh)结合部位的细胞外结构域;4个跨膜结构域(M1~4),其中M2的大部分氨基酸位于离子通道的内壁;一个胞质噜扑(loop)和一个胞外C端。通道门位于孔道内的疏水区。ACh结合部位位于天然和功能受体的两个亚基的界面,是由一个亚基的3个噜扑(A-C)和另一个亚基的3个噜扑(D-F)构成。每当受体与ACh(或其他激动剂)分子结合时,M2 α螺旋体的构象发生改变,使通道开启,处于阳离子传导状态,直至一个或两个激动剂分子从结合口袋解离,通道才关闭。如果激动剂一直存在,并反复结合,则通道处于脱敏状态。nAChRs与新烟碱类的各种选择性作用取决于新烟碱类的结构以及nAChRs的亚基组成。     

杀虫剂分子靶标烟碱型乙酰胆碱受体研究进展

昆虫烟碱型乙酰胆碱受体(nicotinic acetylcholine receptors,nAChRs)广泛分布于昆虫中枢神经系统,是杀虫剂作用的主要靶标。目前昆虫中该受体的天然亚基组成尚不完全明确。果蝇的任意α亚基与脊椎动物的一个β亚基共表达是目前最好的异源表达模型,但仍然急需新的研究工具,研究表明一些与受体相关的蛋白质影响着表达。胞内磷酸化的调节作用为今后受体药理学特性的研究提供了新方向。受体亚基上一些关键氨基酸在新烟碱杀虫剂对受体的选择作用中起重要作用。在对吡虫啉抗性的褐飞虱种群中找到了与抗性相关的突变位点,这为新烟碱类杀虫剂靶标不敏感性研究提供了直接证据。对昆虫烟碱型乙酰胆碱受体的分子多样性、功能表达、胞内调节机制、受体与杀虫剂的选择作用及其抗性分子机理等的研究进展进行了综述。     

害虫对新烟碱类杀虫剂的抗药性及其治理策略

烟碱和新烟碱类杀虫剂都是作为后突触烟碱乙酰胆碱受体(nAChRs)的激动剂作用于昆虫中枢神经系统,但这两类杀虫剂存在明显不同的选择毒性:烟碱类对哺乳动物毒性较高,而杀虫活性低;新烟碱类具有高杀虫活性,而对哺乳动物低毒。由于新烟碱类杀虫剂的作用方式独特,对以前使用的如拟除虫菊酯类、氯化烃类、有机磷类和氨基甲酸酯类等杀虫剂很少或无交互抗性,该类杀虫剂为防治一些世界性重大害虫(包括对以前使用的杀虫剂具有长期抗性的害虫)作出了重要贡献。但现已发现不少害虫对新烟碱类杀虫剂产生了抗性。文章就害虫对新烟碱类杀虫剂的抗性概况、抗性机理和抗性治理策略进行了综述。     

新烟碱类杀虫剂毒理学研究进展

以吡虫啉和啶虫脒为代表的新烟碱类杀虫剂具有卓越的内肖活性及很高的残留活性。放射配基结合实验表明，新烟碱类杀虫剂对多种昆虫乙酰胆碱受体具有高亲和力，乙酰胆碱是其竞争性结合抑制剂，电生理学研究表明，该类杀虫剂与乙酰胆碱类似，可诱导瞬时内向电流，并可作用于药理学性质不同的昆虫烟碱型乙酰胆碱受体（nAChR)亚型，分子生物学研究进一步表明，该类杀虫剂主要作用于昆虫nAChRα亚基。     

绿色农药环氧啉的开发及应用

绿色农药环氧啉,是具有自主知识产权,我国首创超高效农药. 分子式: C6H10N4O3 分子量: 186 化学名称:1-(2,3-环氧丙基)-N-硝基亚咪唑烷-2-基胺 针对新烟碱类化合物的结构特点,本研究基于计算机辅助 药物分子设计(CADD)方法,利用COMFA模拟结果,以4个含不同药效团的活性中间体为原料合成了一系列新烟碱类化合物.     

新烟碱类杀虫剂对蜜蜂亚致死效应的研究进展

蜜蜂是一种经济型昆虫,其授粉作用在农业生产、濒临植物保护等方面具有重要意义。新烟碱类杀虫剂的广谱性、高效性、对哺乳动作的低毒性使得这类药剂备受人们关注,被广泛使用在农业生产生活中。近年来,新烟碱类杀虫剂对蜜蜂的潜在威胁也成为研究的热点,特别是对蜜蜂亚致死效应的研究。本文简要介绍了新烟碱类杀虫剂的应用概况及其作用机理,重点阐述了亚致死剂量的新烟碱类杀虫剂对蜜蜂生长发育及行为等的影响,并提出了几个有待进一步研究解决的问题,以期为我国新烟碱类杀虫剂对蜜蜂的安全性评价工作提供参考信息。     

新烟碱类杀虫剂的作用机制、应用及结构改造的研究进展

新烟碱类杀虫剂具有高效、低毒、广谱、选择毒性强和对环境安全等现代提倡的有机农药特点,是目前常用的最佳杀虫剂品种之一。本文结合最新进展,介绍了新烟碱类杀虫剂及其受体的结构特点、作用机制、应用及新烟碱类杀虫剂化合物分子结构改造等方面的研究。     

新烟碱类杀虫剂吡虫啉和噻虫嗪的代谢研究进展

对新烟碱类杀虫剂吡虫啉和噻虫嗪的化学结构特点及代谢研究进展进行了综述,重点对其在哺乳动物、植物和昆虫体内的代谢途径及相关的生物代谢酶进行了阐述。吡虫啉和噻虫嗪在环境中可被动物、植物、微生物及昆虫所代谢,与其生物代谢相关的酶主要是微粒体细胞色素P450同工酶和醛氧化酶,其中,P450同工酶可催化吡虫啉和噻虫嗪发生羟基化、去饱和、脱烷基、硝基还原等代谢反应,而醛氧化酶主要催化其硝基部分的还原。吡虫啉和噻虫嗪经过代谢后其生物活性通常有所降低,但也有部分代谢产物的活性反而升高,增加了其对昆虫的毒性以及对非靶标生物的风险。明确吡虫啉和噻虫嗪的代谢途径、代谢产物及其生物活性,对于了解新烟碱类杀虫剂的代谢机理,以及安全有效地使用该类杀虫剂具有重要意义。     

Sulfoxaflor and the sulfoximine insecticides: Chemistry,mode of action and basis for efficacy on resistant insects

The sulfoximines, as exemplified by sulfoxaflor ([N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-λ⁴-sulfanylidene] cyanamide] represent a new class of insecticides. Sulfoxaflor exhibits a high degree of efficacy against a wide range of sap-feeding insects, including those resistant to neonicotinoids and other insecticides. Sulfoxaflor is an agonist at insect nicotinic acetylcholine receptors (nAChRs) and functions in a manner distinct from other insecticides acting at nAChRs. The sulfoximines also exhibit structure activity relationships (SAR) that are different from other nAChR agonists such as the neonicotinoids. This review summarizes the sulfoximine SAR, mode of action and the biochemistry underlying the observed efficacy on resistant insect pests, with a particular focus on sulfoxaflor.     

Thiamethoxam acts as a target‐site synergist of spinosad in resistant strains of Frankliniella occidentalis

BACKGROUND: Previous studies have suggested that the resistance mechanism towards spinosad in Frankliniella occidentalis (Pergande) is an altered target site. Like the neonicotinoids, the spinosyns act on nicotinic acetylcholine receptors (nAChRs) in insects, but at a distinct site. The changes in nAChRs related to spinosad resistance in thrips might involve interaction with neonicotinoids. In this study, the efficacy of spinosad and neonicotinoids, alone and in combination, was evaluated in susceptible and spinosad‐resistant thrips strains. RESULTS: The neonicotinoids tested were imidacloprid, thiacloprid, acetamiprid, thiamethoxam and clothianidin. No cross‐resistance was shown between spinosad and any of the neonicotinoids. However, an increased toxicity was observed when a mixture of spinosad with thiamethoxam or clothianidin was tested. No synergism was found in the susceptible strains. The more spinosad‐resistant the thrips strain, the stronger was the synergism. CONCLUSION: Data suggest that spinosad and thiamethoxam may interact at the nAChRs in spinosad‐resistant thrips, facilitating enhanced insecticidal action. Copyright © 2012 Society of Chemical Industry     

Neonicotinoids-from zero to hero in insecticide chemistry

In recent years, neonicotinoids have been the fastest-growing class of insecticides in modern crop protection, with widespread use against a broad spectrum of sucking and certain chewing pests. As potent agonists, they act selectively on insect nicotinic acetylcholine receptors, their molecular target site. The discovery of neonicotinoids can be considered as a milestone in insecticide research and facilitates greatly the understanding of the functional properties of insect nicotinic acetylcholine receptors. Because of the relatively low risk for non-target organisms and environment, the high target specificity of neonicotinoid insecticides and their versatility in application methods, this important class has to be maintained globally for integrated pest management strategies and insect resistance management programmes. This review comprehensively describes particularly the origin, structure and bonding as well as associated properties of neonicotinoid insecticides.     

Correlations of the electrophysiological activity of neonicotinoids with their binding and insecticidal activities

The electrophysiological actions of various neonicotinoids, including substituted benzyl derivatives, against recombinant Drosophila SAD/chicken beta2 hybrid nicotinic acetylcholine receptor (nAChR) were measured to analyze the relationships between the in vivo (insecticidal) and in vitro (binding and agonist) activities. Most of the neonicotinoids tested were capable of inducing inward currents by activating the hybrid nAChRs expressed in Xenopus laevis oocytes, whereas some compounds had no agonist activity and only blocked the acetylcholine-induced currents. Variations in the agonist activity were well correlated with those in the binding potency evaluated using [3H]imidacloprid as well as insecticidal activities.     

Comparative analysis of neonicotinoid binding to insect membranes: I. A structure-activity study of the mode of [3H]imidacloprid displacement in Myzus persicae and Aphis craccivora

Neonicotinoids bind selectively to insect nicotinic acetylcholine receptors with nanomolar affinity to act as potent insecticides. While the members of the neonicotinoid class have many structural features in common, it is not known whether they also share the same mode of binding to the target receptor. Previous competition studies with [3H]imidacloprid, the first commercialised neonicotinoid, indicated that thiamethoxam, representing a novel structural sub-class, may bind in a different way from that of other neonicotinoids. In the present work we analysed the mode of [3H]imidacloprid displacement by established neonicotinoids and newly synthesized analogues in the aphids Myzus persicae Sulzer and Aphis craccivora Koch. We found two classes of neonicotinoids with distinct modes of interference with [3H]imidacloprid, described as direct competitive inhibition and non-competitive inhibition, respectively. Competitive neonicotinoids were acetamiprid, nitenpyram, thiacloprid, clothianidin and nithiazine, whereas thiamethoxam and the N-methyl analogues of imidacloprid and clothianidin showed non-competitive inhibition. The chloropyridine or chlorothiazole heterocycles, the polar pharmacophore parts, such as nitroimino, cyanoimino and nitromethylene, and the cyclic or acyclic structure of the pharmacophore were not relevant for the mode of inhibition. Consensus structural features of the neonicotinoids were defined for the two mechanisms of interaction with [3H]imidacloprid binding. Furthermore, two sub-classes of non-competitive inhibitors can be discriminated on the basis of their Hill coefficients for imidacloprid displacement. We conclude from the present data that the direct competitors share the binding site with imidacloprid, whereas non-competitive compounds, like thiamethoxam, bind to a different site or in a different mode.