1、Insecticides mode of action,Mode of Action of Insecticides,Nerve poisons (axonic and synaptic) Metabolic inhibitors Muscle poisons Alkylating agents Physical toxicants Cytolytic (cellular) toxins,USDA/ARS,一、Nerve Poisons,突触抑制剂Synaptic poisons:1、有机磷：抑制AchE 2、氨基甲酸酯：抑制AchE 3、沙蚕毒素类：占领nAchR降低后膜敏感性。 4、杀虫脒
2、：激活章鱼胺受体，抑制单胺氧化酶，阻断神经传导。,一、Nerve Poisons,突触抑制剂Synaptic poisons: 5、烟碱及其类似物: AchR, 模仿Ach 6、 Avermectins、锐劲特：激活GABAa受体，氯离子通透性改变，后膜超极化，神经传导被抑制。,一、Nerve Poisons,突触抑制剂Synaptic poisons: 7、多杀菌素: 作用CNS，显示nAchR被持续激活引起的Ach延长释放效应。同时还作用于GABAa受体，影响氯离子通道功能。 激活GABAa受体，氯离子通道开放，大量氯离子进入。后膜超极化。,一、Nerve Poisons,轴突抑制剂Axo
3、nic poisons: 8、DDT, pyrethrum and synthetic pyrethroids,Mode of Action of Insecticides,二、代谢抑制剂： 鱼藤酮、砷制剂、HCN、CO 三、肌肉毒剂: 直接作用在肌肉组织上，如 ryania（鱼尼汀） and sabadilla（藜芦碱） 增加氧的消耗，造成麻痹和死亡 四、烷基化试剂（Alkylating agents）: react directly with chromosomes and enzymes in cells; examples are fumigants such as methyl br
4、omide and ethylene dibromide,Mode of Action of Insecticides,五、物理毒剂（Physical toxicants）: mechanically blocks a physiological process; examples are oil (blocks respiratory openings in insects) and boric acid and silica gel (effects insect cuticle causing dehydration and death) 六、细胞毒剂Cytolytic (cellula
5、r) toxins: cause cells to rupture破损 and disintegrate解体; example is Bacillus thuringiensis which is ingested by insects and disrupts cells in the gut (causing paralysis of gut and cessation of feeding),树突,轴突,胞体,终球,髓鞘,突触,DJS,Affects on Nerves,How Insecticides & Miticides Work,DJS,Affects on Nerves,How
6、 Insecticides & Miticides Work,DJS,Affects on Nerves,How Insecticides & Miticides Work,囊胞与突触前膜接触，乙酰胆碱扩散到突触内 乙酰胆碱与突触后膜的乙酰胆碱受体结合,受体上有钠离子通道，正常情况下，钠离子通道是关闭的。,乙酰胆碱与乙酰胆碱受体结合使钠离子通道开放 钠离子涌入，使后膜脱极化,钠离子通道是如何关闭的？ 乙酰胆碱酯酶将乙酰胆碱分解，使钠离子通道关闭,囊胞与突触前膜接触，乙酰胆碱扩散到突触内 乙酰胆碱与突触后膜的乙酰胆碱受体结合,总结,一、正常神经传导过程 神经传导是一种电化学过程。正常神经细胞膜处
7、于一种电极化状态，存在一个外正内负的电位差。外面的钠离子不能自由进入。当神经元胞体和树突受到刺激时，膜透性改变，钠离子进入膜内，使膜脱极化，形成冲动。冲动延轴突传导。 当神经冲动传至神经末梢时膜的离子透性改变钙离子进入终球囊胞与突触前膜接触Ach释放并进入突触间隙与突触后膜的AchR结合 突触后膜钠离子通道开放，电位发生变化，神经细胞之间的信号传导完成。,总结,信号传导完成以后，AchE将Ach分解成乙酰和胆碱，它们有回到突触前膜，在乙酰辅酶A的作用下又合成Ach，继续进行另一个神经传导。 二、有机磷对神经传导作用 有机磷抑制AchE，使其不能分解Ach，过量的Ach与AchR结合，正常神经传
8、导释放的Ach不能与AchR结合。突触后膜钠离子通道持续开放，因而阻断了正常的神经传导。,ATROPINE,ATROPINE,ATROPINE,ATROPINE,ATROPINE,ATROPINE,ATROPINE,ATROPINE,ATROPINE,ATROPINE,ATROPINE,ATROPINE,ATROPINE,ATROPINE,ATROPINE,Hydrolysis of Acetylcholine,N,H3 C,H3 C,CH3,CH2,CH2,C-CH3,O,O,Esterophilic,Anionic,+,Acetylchoine esterase,Choline,Aceti
9、c acid,Regenerated Enzyme,3x105 Ach mol./mol.of enzyme-150 usec.,+,Acetyl Co-A,+ H2O,Action.at nerve synapse,acetylcholine,O,+,N,O,OH,O,HO,+,N,Acetylcholine,O| + CH3-C-O- + HO-CH2-CH2-N-(CH3)3,Nerves and Pyrethroids,Sodium Channels,Direction of Nerve Impulse,Spinosyns,Saccharopolyspora spinosa ferme
10、tation product Soil dwelling Success*, Naturalyte*, Tracer* (Dow AgroSciences) Testing for UPM,MOA: GABA Antagonist,Phenylpyrazole (fipronil), cyclodienes Antagonists of GABA activated chloride channels GABA Antagonists: chemicals that bind to but do not activate GAMMA-AMINOBUTYRIC ACID receptors, t
11、hereby blocking the actions of endogenous GAMMA-AMINOBUTYRIC ACID or GAMMA-AMINOBUTYRIC ACID agonists. GABA cant bind to receptor Doesnt activate channel (doesnt open) Interferes with (prevents) the passage of chlorine ions through the channel. Concerns with cross resistance with other GABAergic ins
12、ecticides,GABA Receptor in Central Nervous System,Phenylpyrazoles or Fiproles,GABA-receptors,GABA,Phenyl pyrazoles,Fipronil Chipco Choice - mole crickets & grubs Firestar, Ouver-N-Out, (Ceasefire)-fireants Termidor - termites Regent - corn Frontline - flea & tick MaxForce FC - cockroaches and ants,M
13、ost lipophilic insecticide ever discoveredPersistent in soilSpread among social insects on bodies4 months of residual on dogs (binds to oils in sebaceous glands),MOA: GABA Agonist,Avermectins Bind to GABA (Gamma-Amino-Butyric Acid gated chloride channel Opens channel Chloride influx Cannot reach thr
14、eshold for action potential Causes membrane to hyperpolarize, making it less excitatory, decreasing nerve transmission Result: flaccid paralysis and death,Avermectins,Abamectin Avert - cockroaches Advance - ants,Produced from soil microbials. Stomach poison for ants and cockroachesslow actinglow tox
15、icity to mammals,Nervous System,Why does this happen? Lets look at a “normal” nerve impulse.,“Diagram of a neuron illustrating the subcellular locations of voltage-gated sodium channels.”,#4. Myelinated,#3. Unmyelinated,#6. Apical dendrites,#5. Presynaptic #7. Postsynaptic,U of Colorado Health Scien
16、ce,Rensselar Polytechnic Institute,Axon Membrane at Rest,“Leaky membrane” K+: many leaky channels Na-: few leaky channels Outside: Na- Inside: K+,Axon Membrane,Rensselar Polytechnic Institute,An action potential is initiated whenever there is a stimulus. A stimulus is an event that causes depolariza
17、tion or decrease in the membrane potential,Axon Membrane,Opening of external Na gates Results in influx of Na,Axon Membrane,Eventually reach Na equilibrium,Axon Membrane,As a result of the depolarization, the internal Na+ gates shut and remain closed for about millisecond. The rapid decrease causes
18、the membrane potential to return to the K equilibrium potential.,Bacillus thuringiensis - microbial toxins,crystal proteins,Bt,different strains reasonably specific to different insect groups mode of action: some how destroys gut of caterpillar,Mode of Action of Organophosphates,F,O,P,OC3H7,H7C3O,N:
19、-H-O,Anionic,Esteratic,P,OC3H7,O,H7C3O,F,N:-H-O,N:-H-O,Phosphorilated enzyme,Mode of Action of 2-PAM,H7C3O-P-OC3H7,O,N:,O,Esteratuc,Anionic,CH3,N+,C=N-OH,H,Pyridine 2-Aldoxime,+,O,N:,-,-,-,Mode of Action of 2-PAM,N+,CH3,C=N-O-P,O,OC3H7,H7C3O,N:H-O,Regenerated Enzyme,Oxime-phosphonate,Kidneys,_,Electrophilic,Nucleophilic,H3C-N-C-O-,H,O,N,N,CH3,Physostigmine,CH3,CH3,H3C H3C,N-C-,O,O,N+ (CH3 )3,Pyridostigmine,Cyclodienes,Cyclodienes,
