1、1,拟除虫菊酯类杀虫剂,Pyrethroid insecticide Pyrethrum(除虫菊) is found in the flowers of plants belonging to the family Compositae(菊科) and the genus Chrysanthemum(菊属). Originally pyrethrum flowers came from Yugoslavia(南斯拉夫) and Japan, but Kenya(肯尼亚) now supplies most of them.,2,第四章 拟除虫菊酯类杀虫剂药理学,白花除虫菊和红花除虫菊,3,第四
2、章 拟除虫菊酯类杀虫剂药理学,Pyrethrum powders were first used around 1800, and by 1851 their use was world-wide. The ground flowers can be used as an insecticide, but this is very wasteful. Pyrethrum concentrates may be prepared from the ground flowers by extracting with petroleum ether(石油醚), acetone, glacial ac
3、etic acid(冰醋酸), ethylene dichloride(二氯乙烷), or methanol.,4,第四章 拟除虫菊酯类杀虫剂药理学,Technical pyrethrum contains 2030% of the toxic ingredient, and after filtration(过滤) and reextraction the concentrate contains 90100% pyrethrins(除虫菊酯).,5,Pyrethrum is essentially nontoxic to mammals (acute oral LD50 in rats a
4、bout 1500mg/kg) and is very fast-acting toward insects. It rapidly paralyzes insects, especially houseflies, and is commonly used in fly sprays and household insecticides. Often DDT or other insecticides are mixed with the pyrethrins because insects may later recover from pyrethrum alone.,第四章 拟除虫菊酯类
5、杀虫剂药理学,6,第四章 拟除虫菊酯类杀虫剂药理学,Pyrethrums are highly unstable in the presence of light, moisture, and air. Whole flowers decompose(分解) more slowly than ground flowers or dust. Stored powders lose about 20% of their potency in 1 year.,7,synthetic pyrethrin The pyrethrin compounds are viscous(黏稠的) liquids
6、which are insoluble in water but soluble in organic solvents and oils. They are hydrolyzed in water, and the process is speededy acid or alkali.,第四章 拟除虫菊酯类杀虫剂药理学,8,The pyrethins are contact insecticides and have almost no stomach poison action because they are so readily hydrolyzed to nontoxic produ
7、cts. Their primary action is on the insect central nervous system, as shown by the fact that they produce such rapid paralysis.,第四章 拟除虫菊酯类杀虫剂药理学,9,一、拟除菊酯类杀虫剂的发展,Allethrin(丙烯除虫菊酯) was the first synthetic pyrethrum analogue(1954). The synthetic pyrethrins are more stable than the natural pyrethrins du
8、e to the lower reactivity of the side-chains. Allethrin is cheap to produce and is effective against to houseflies.,10,一、拟除菊酯类杀虫剂的发展,The initial breakthrough was certainly the discovery of the feasibility of aromatic substitutions such as the ones shown below, of which resmethrin(苄呋菊酯) is the most o
9、utstanding insecticide.,11,一、拟除菊酯类杀虫剂的发展,The most significant development was perhaps the discovery of a phenothrin(苯醚菊酯)-type alcohol substituent.,12,一、拟除菊酯类杀虫剂的发展,The next breakthrough came when Elliots group found high insecticidal activity among the phenothrin analogues in which the vinylmethyl(
10、乙烯基甲) moiety is replaced by halogens(卤族)(e.g. permethrin氯菊酯),13,一、拟除菊酯类杀虫剂的发展,With the modification of both alcohol and acid sides, they are also becoming stable enough to be used for agricultural purposes.,14,一、拟除菊酯类杀虫剂的发展,Next came the finding that the addition of a cyano(氰基) group at the -positio
11、n of the alcohol moiety increases insecticidal activity (e.g., cypermethrin氯氰菊酯). Decamethrin ( deltamethrin溴氰菊酯), a brominated(溴化物) relative of cypermethrin, is said to be one of the most potent insecticidal pyrethroids ever developed.,15,一、拟除菊酯类杀虫剂的发展,Cypermethrin consists of eight isomers, four c
12、is and four trans isomers, the cis isomers being the more biologically active. Depending on the manufacturing source, the cis:trans ratio varies from 40:60 to 80:20.,16,一、拟除菊酯类杀虫剂的发展,Another breakthrough came when the Sumitomo(住友) group discovered that it is even possible to substitute the cycloprop
13、ane (环丙) ring of the acid side, the structure that had been regarded as an essential moiety for the pyrethrin-like activity.,17,一、拟除菊酯类杀虫剂的发展,Fenvalerate(氰戊菊酯) is a pyrethroid that no longer holds any resemblance(相像) to natural pyrethrins.,18,一、拟除菊酯类杀虫剂的发展,This particular modification, although it d
14、id not appreciably(明显地) increase insecticidal activity, made the synthetic processes easier and as a consequence the product more economical.,19,一、拟除菊酯类杀虫剂的发展,Cyhalothrin(氯氟氰菊酯) was developed in 1977. Lambda-cyhalothrin is mainly used as an agricultural pesticide on a wide range of crops and is bein
15、g developed for public health.,20,二、菊酯类杀虫剂的作用机理,Modes of action of pyrethroid insecticides: (1) repellent action: sense organ; sensorium(知觉器官) (2) knockdown action: peripheral nervous system (3) poisoning action Central nervous system (CNS),21,二、菊酯类杀虫剂的作用机理,Pyrethrum is an insecticide well known for
16、 its quick knockdown action or, more precisely, its induction of temporary paralysis. This unique action does not necessarily represent the killing property: the amount required to produce mortality is usually much greater than that for paralysis.,22,二、菊酯类杀虫剂的作用机理,The primary target of the pyrethrin
17、 group of insecticides is considered to be the nervous system, as judged by their quick action and the results of symptomatological(病征学的) studies. The symptoms of pyrethrin poisoning follow the typical pattern of nerve poisoning :(1) excitation, (2)convulsions(抽搐), (3)paralysis, and (4)death.,23,二、菊
18、酯类杀虫剂的作用机理,Electrophysiologically, pyrethrins cause repetitive discharges(重复放电) and conduction block. There are two types of pyrethroid action and that pyrethrin and allethrin(丙烯菊酯) are typical of the first type and fenvalerate(氰戊菊酯), cypermethrin(氯氰菊酯) and decamethrin(溴氰菊酯) typical of the second. I
19、t is also clear that typical Type I actions closely resemble those of DDT.,24,二、菊酯类杀虫剂的作用机理,Type I action is mainly associated with compounds that cause nerve excitation symptoms typified by the appearance of repetitive discharges and a negatively correlated temperature reversible knockdown property
20、.,25,二、菊酯类杀虫剂的作用机理,Type II action is related to the positively temperature correlated killing action and the nerve blocking action.,26,二、菊酯类杀虫剂的作用机理,As for the molecular basis of the mechanism of action of pyrethroids, most workers agree that Type I pyrethroids act largely through a mechanism identi
21、cal to that of DDT. The most prominent reason cited for this conclusion is the cross-resistance exhibited by kdr-type DDT-resistance insects to Type I pyrethroids.,27,二、菊酯类杀虫剂的作用机理,It has been reported that Type II pyrethoids affect the sodium channel operations in a different manner from Type I pyr
22、ethoids.,28,二、菊酯类杀虫剂的作用机理,钠离子通道,29,二、菊酯类杀虫剂的作用机理,钠离子通道,30,二、菊酯类杀虫剂的作用机理,The principle subunit of the voltage-gated sodium channel is a polypeptide chain of more than 1800 amino acids. In the case of the voltage-gated sodium channel, there are 24 such transmembrane alpha-helices in the polypeptide,31
23、,二、菊酯类杀虫剂的作用机理,钠离子通道,32,二、菊酯类杀虫剂的作用机理,钠离子通道,33,二、菊酯类杀虫剂的作用机理,In the case of the voltage-gated sodium channel, the gate is controlled by a voltage sensor, which responds to the level of the membrane potential.,34,二、菊酯类杀虫剂的作用机理,http:/courses.washington.edu/conj/membrane/nachan.htm,35,二、菊酯类杀虫剂的作用机理,The
24、 interaction of pyrethroids with the sodium channel has the effect of slowing both the activation and inactivation properties of the sodium channel.,36,二、菊酯类杀虫剂的作用机理,In the phase of the action potential even the low proportion of modified channels can generate enough extra current to delay inactivat
25、ion. This slower rate of inactivation of pyrethroid-modified channels generates a prolonged depolarizing “tail” current.,37,二、菊酯类杀虫剂的作用机理,This “tail” can trigger a second action potential if the current is large enough and lasts for more than 0.5 ms.,38,二、菊酯类杀虫剂的作用机理,Another significant feature is t
26、hat, after modification by pyrethroids, sodium channels retain many of their normal function. This means that after exposure to moderate doses of pyrethroids cells can continue to function, but in a new and relatively stable state of abnormal hyper-excitability.,39,二、菊酯类杀虫剂的作用机理,In insects this stat
27、e corresponds to the incapacitating(使无能力) but sublethal effect known as “knock down”.,40,二、菊酯类杀虫剂的作用机理,An important characteristic of the pyrethroid-generated tail current is that the amplitude(振幅) and duration are independent. The current amplitude is dependent only on the proportion of sodium chan
28、nels modified, and hence shows a sigmoid(S形的) relationship with concentration or dose.,41,二、菊酯类杀虫剂的作用机理,The current duration is dependent only on the pyrethroid structure. Individual pyrethroids thus generate a characteristic time constant for prolongation of the sodium channel tail current that is
29、virtually(差不多) independent of dose.,42,二、菊酯类杀虫剂的作用机理,There is a continuous distribution of time constants(恒定的) across the range of pyrethroid structures, with type I pyrethroids producing the shorter time constants, and type II pyrethroids producing the longer time constants.,43,二、菊酯类杀虫剂的作用机理,Pyreth
30、roid action on the sodium channel shows a marked stereospecificity(立体特异性) that results in some isomers being far more toxic than others.,44,二、菊酯类杀虫剂的作用机理,Differential toxicity of isomers In mammals the 1R isomers are active and the 1S isomers inactive and essentially non-toxic. The cis isomers being
31、 about 10 times more potent than the trans isomers.,45,二、菊酯类杀虫剂的作用机理,46,二、菊酯类杀虫剂的作用机理,Some potential targets of pyrethroids in mammals Voltage-gated sodium channels Voltage-gated chloride channels Voltage-gated calcium channels GABA-gated chloride channels Protein phosphorylation,47,二、菊酯类杀虫剂的作用机理,So
32、me potential targets of pyrethroids in mammals Noradrenaline(去甲肾上腺素) release Membrane depolarization Nicotinic receptors Mitochondrial complex Mitochondrial ATP-ase,48,二、菊酯类杀虫剂的作用机理,DDT, permethrin（氯菊酯), and deltamethrin(溴氰菊酯) substantially(大大地) enhanced the release of -aminobutyric acid(GABA) from
33、synaptosomes(突触体) isolated from the guinea pig cortex(豚鼠大脑皮层). With respect to biochemical actions of pyrethroids, pyrethroids are good inhibitor of Ca-Mg and Ca-ATPases of the axolemma(轴膜) preparation.,49,二、菊酯类杀虫剂的作用机理,1、对脑组织生物膜影响 （1）、对膜流动性影响 含氰基的型拟除虫菊酯可降低膜表面负电荷密度及膜的流动性，增加脂双层极性头部的活动程度，不含氰基的型拟除虫菊酯能增
34、加膜的流动性，但对脂双层极性头部的活动无明显影响 。,50,二、菊酯类杀虫剂的作用机理,1、对脑组织生物膜影响 （2）、对膜结合酶影响 可明显抑制寡霉素敏感的Mg2+-ATPase活性，并呈一定的浓度-效应关系，未观察到Na+/K+-ATPase和寡霉素不敏感Mg2+-ATPase活性有明显改变，并认为拟除虫菊酯有可能干扰神经系统的能量代谢 。,51,二、菊酯类杀虫剂的作用机理,2、对神经递质的影响 （1）对5-羟色胺递质的影响 （2）对脊髓中氨基酸递质的影响 （3）对兴奋性氨基酸递质的影响 （4）对谷氨酸递质传递过程的影响,52,二、菊酯类杀虫剂的作用机理,3、对神经信号转导过程的影响 （1
35、）对大鼠大脑皮层突触膜谷氨酸受体结合的影响 （2）对大鼠脑神经元胞内游离钙的影响 （3）对脑细胞肌醇磷脂代谢的影响,53,二、菊酯类杀虫剂的作用机理,4、对神经细胞损伤机理 （1）对脂质过氧化水平的影响 （2）对神经细胞凋亡的诱发作用 （3）对脑细胞肌醇磷脂代谢的影响 溴氰菊酯对大鼠神经细胞凋亡的诱发作用，表现为分离的神经细胞DNA受到损伤，出现类似凋亡的形态学改。,54,三、菊酯类杀虫剂的中毒及其治疗,Pyrethroids have little or no direct cytotoxic(细胞毒素的) potential in mammalian cell. Studies of ge
36、notoxicity(致突变) and carcinogenicity(致癌) have either proved negative or indicated little toxic potential. The nervous system is the primary target.,55,三、菊酯类杀虫剂的中毒及其治疗,The relative resistance of mammals to pyrethroids is due to: Faster metabolic disposal(清理) Higher body temperature (negative temperatu
37、re coefficient) Lower sensitivity of target sites,56,三、菊酯类杀虫剂的中毒及其治疗,Low volatility(挥发性): inhalation insignificant Slow absorption through the skin Rapid hydrolysis in blood and liver Pyrethroids (high lipophilicity) rapidly distribute through the body (into the brain),57,三、菊酯类杀虫剂的中毒及其治疗,Type I pyre
38、throids produce the simplest poisoning syndrome and produce sodium tail currents with relatively short time constants. Type II pyrethroids produce a more complex poisoning syndrome and act on a wider range of tissues.,58,三、菊酯类杀虫剂的中毒及其治疗,In addition to systemic toxicity, sufficiently high doses of pyrethroids can produce important local effects: skin contamination (paraesthesia感觉异常), gastrointestinal irritation(肠胃不适), respiratory tract irritation(呼吸道刺激).,59,三、菊酯类杀虫剂中毒后的治疗,1、对痉挛者：巴比妥、苯妥英、氨甲酰甘油愈创木酚醚 2、对唾液分泌过多者：阿托品,
