氨基甲酸酯类杀虫剂药理学课件

1 Chapter3 CarbamateInsecticides 1 DevelopmentThecarbamateinsecticidesarethelatestarrivalinthefieldofanticholinesteraseinsecticides andatpresentmanynewcompoundsarestillintheprocessofbeingmarketed 2 CarbamateInsecticides Ingeneral carbamateinsecticidesaresyntheticderivativesofphysostigmine commonlycalledeserine whichistheprincipalalkaloidoftheplantPhysostigmavenenosum calabarbeans 3 CarbamateInsecticides Physostigmavenenosum calabarbeans 4 CarbamateInsecticides TheChemicalstructureofeserinewasanalysedin1925 5 CarbamateInsecticides Physostigminewasknowntobeaninhibitorofcholinesterase andStedmanandEason 1932 workedtodevelopsyntheticanalogues suchasprostigmine 6 CarbamateInsecticides Althoughtheseandsimilarcompoundsareeffectiveinhibitorsofinsectcholinesterase theyareunsuitableasinsecticides fortheyarewater solublequaternarysaltsoraminehydrochloridesandhencetoopolartopenetratetheinsectcuticle 7 CarbamateInsecticides Kolbezenattributedtheirineffectivenessasinsecticidestotheirlowlipoidsolubility O Brienconsideredthattheion impermeablesheathoftheinsectnervewouldalsocontributetotheirineffectiveness forthesedrugswereionizedatphysiologicalpHandwouldthereforebeexcludedfromtheirsiteofaction 8 CarbamateInsecticides Hencethemoderncarbamateinsecticideshavebeenmodifiedbyeliminatingthepolarmoietyofphysostigminesothattheycaneasilypenetratetheinsectcuticleaswellasthenervesheath 9 CarbamateInsecticides ThegeneralcarbamatestructureisO R1NH C OR2whereR1andR2arealkylorarylgroups 10 CarbamateInsecticides 1 Carbofuran 克百威 呋喃丹 ishighlytoxic withanacuteoralLD50inratsof5mg Kg Itiseffectiveagainstsoilinsectsincorn cottoninsects andpestsonpotatoes 11 2 Temik aldicarb isanewtypeofsystemiccarbamateinsecticide acaricide andnematocidewhichisabsorbedintotherootsystemofplantsandhasaresiduallifeofupto10weeks Temikishighlytoxic withanacuteoralLD50inratsof1 30mg kg Itisrelativelysolubleinwater CarbamateInsecticides 12 CarbamateInsecticides 3 Methomylisawhitecrystallinesolid Itisfairlysolubleinwater Itsacuteoraltoxicitytoratsis17mg kg Ithas however alowdermaltoxicity 5000mg kg rabbits Itisabroad spectruminsecticideonvariousvegetables forage 草料 andsomeornamentals 13 CarbamateInsecticides 4 Propoxurisacontactinsecticidewhichshowssystemicactionwithsoilapplication Ithasarapidknockdownandhasalongresiduallife Itiseffectivelyusedagainstcockroaches flies mosquitoes chinchbugs andspiders 14 Actionmechanism InhibitionofAChE1 coulombicbinding2 carbamylation phosphorylation 3 decarbamylation dephosphorylation 15 Actionmechanism Carbamatesarepowerfulanticholinesteraseagents andactinmammalsasparasympathomimetic 拟副交感 神经 的 类副交感 神经 的 drugs 16 Actionmechanism Clinicallytheyareusedas 1 drugsfortopicaladministrationasmiotic 缩瞳剂 inglaucoma 青光眼 2 stimulantsofintestinalperistalsis 蠕动 3 drugsfortreatmentofurinaryretentionandformyastheniagravis 肌肉衰弱 andmusclespasms 肌肉痉挛 17 Actionmechanism Thebasicdifferencebetweenmedicalandinsecticidalcarbamatesisthattheformercompoundsalwayspossesseitheraquaternaryorabasicnitrogengroupwhichcanattacktheanionicsiteofcholinesterase whereasthelattercompoundsareneverbasic i e ionizationreducestheabilityofthecompoundstopenetratetheinsectcuticleaswellasthenervesheath 18 Actionmechanism 1 SymptomsThesymptomsininsectsareprimarilythoseofpoisoningofthecentralnervoussystem Theactionofthecarbamatemaybeblockedbyapplicationofnicotine atropine 阿托品 orbarbituricacid 巴比妥酸 totheganglion 神经节 19 Actionmechanism CarbamatesareeffectiveinsecticidesbyvirtueoftheirabilitytoinhibitAChEinthenervoussystem Thesiteforcarbamylationoftheenzymeisthehydroxylmoietyoftheserineaminoacid 20 Actionmechanism Carbamatesareaspotentcholinesteraseinhibitorsasorganophosphatesare andtheybehaveinanalmostidenticalmannerinbiologicalsystems withcertaindifferences 21 Actionmechanism Certaincarbamatesareveryselectiveinhibitorsofcholinesteraseandnotofaliesterase Theselectivityofcarbamatesissometimemorepronounceagainstthecholinesterasesofdifferentspecies 22 Actionmechanism Thesecondimportantdifferencebetweentheactionmechanismofcarbamatesandthatoforganophosphatesisthattheprimarymodeofcholinesteraseinhibitionbycarbamatesisapparentlyreversible 23 Actionmechanism Thereareonefactorcontributingtothisreversibility Thestep3reactioniseasyforcarbamates yieldingtheoriginalenzyme whichresultsintheappearanceofrecovery 24 Actionmechanism Thedecarbamylationprocess step3 canbespeededupbytheadditionofhydroxylaminetotheinhibitedcholinesterase asisthecasewithphosphorylatedcholinesterases butunlikethelattercases 2 PAMdoesnotshowrecoveryactivityonthecarbamylatedenzymes 25 Actionmechanism Theinitialstepofcomplexformation step1 isfavoredbynucleophilicsubstitution whilestep2isenhancedbyelectrophilicsubstitution Incarbamateinhibiton theimportantprocessappearstobestep1 26 Actionmechanism Carbamates likeorganophosphates caninhibitesterasesthathaveserineintheircatalyticcentre thesearecalledserine esterasesorbeta esterases 27 Actionmechanism Althoughtheinhibitionofserine esterasesotherthanAChEisnotsignificantforthetoxicityofthecompounds itmayhavesignificanceforthepotentiationoftoxicityofothercompoundsafterlong termlow levelexposure 28 Actionmechanism ThespontaneousreactivationofvariouscarbamylatedChEsexpressedashalf life atpH7 0 7 4and25 rangedbetween2and240minforAChE 29 Actionmechanism TherateofregenerationofthecarbamylatedenzymetoAChEisrelativelyrapidcomparedwiththatofanenzymethathasbeeninhibited phosphorylated byanorganophosphoruspesticide 30 Actionmechanism MechanismdifferencesbetweencarbamatesandOPinsecticide1 carbamylation phosphorylation2 Selectivityofcarbamateagainstcholinesteraseofdifferentspecies 3 Recoveryspeed4 NoagingforcarbamylatedAChE 5 Therapy Onlyatropineforcarbamylation 31 Actionmechanism CarbamylationAChEserine hydroxylgroupreactwithCarbamate carbonylgroupKi bimolecularrateconstant 32 Actionmechanism I50 0 693 Ki t I50istheconcentrationofinhibitorresultinginlossof50percentoftheenzymat