分子藥理學(xué)課件

分子藥理學(xué)1分子藥理學(xué)1教學(xué)大綱中文名稱分子藥理學(xué)英文名稱MolecularPharmacology

課內(nèi)總學(xué)時(shí)：32教學(xué)方式：講授撰寫人：晏為力考核方式：考試+論文報(bào)告開(kāi)課學(xué)期：

Ⅰ學(xué)分?jǐn)?shù):2內(nèi)容偏重：理論

教學(xué)要求及目的

１．使學(xué)生了解分子藥理學(xué)的基礎(chǔ)知識(shí)和各系統(tǒng)分子藥理學(xué)的進(jìn)展，為從事藥學(xué)基礎(chǔ)研究工作和新藥開(kāi)發(fā)奠定理論基礎(chǔ)。2教學(xué)大綱中文名稱分子藥理學(xué)2課程內(nèi)容內(nèi)容

授課人

日期1．緒論:分子藥理學(xué)研究?jī)?nèi)容,藥物作用的機(jī)制

晏為力9/112．受體藥理及信號(hào)傳導(dǎo)

9/183．細(xì)胞內(nèi)第二信使蛋白激酶及有關(guān)藥物進(jìn)展

9/254．炎癥介質(zhì)與抗炎藥物

10/9

5．抗糖尿病藥物

譚睿10/166．缺血再灌注性損傷的分子機(jī)制

10/23

7．抗體及生物技術(shù)藥物分子藥理學(xué)基礎(chǔ)

喻凱10/308．離子通道和抗心律失常藥理

11/69．高血壓藥的分子藥理學(xué)

11/1310．細(xì)胞色素p450及調(diào)控

11/20

11．神經(jīng)藥理的分子藥理學(xué)基礎(chǔ)

黃新河

11/2712．學(xué)習(xí)、記憶藥理及老年癡呆的藥物干預(yù)

12/413．細(xì)胞凋亡機(jī)理及抗癌藥物研究進(jìn)展

12/1114．氧自由基與抗氧化劑及一氧化氮

12/18

考核方式：

上課情況15%，學(xué)期論文25%，考試60%3課程內(nèi)容內(nèi)容分子藥理學(xué)（MolecularPharmacology)分子藥理學(xué)屬于一門新興學(xué)科，其與傳統(tǒng)藥理學(xué)的最大區(qū)別就在于，它是從分子水平和基因表達(dá)的角度去闡釋藥物作用及其機(jī)制。Theuseoftechniquesofmolecularbiologytoenhancetheunderstandingofthemechanismofactionofexistingdrugs,andwiththehelpofmoleculargraphicstopredictthestructureofnoveldrugs,especiallycompoundsthatmightbindtoproteinsofknownstructure.近代藥理學(xué)的進(jìn)展，主要表現(xiàn)在受體理論、離子通道、信息傳遞、細(xì)胞因子等分子水平上的研究突破。分子藥理學(xué)是指其學(xué)科層次、水平上的科學(xué)性和先進(jìn)性達(dá)到“分子水平”，且又屬于“藥理學(xué)”范疇，分子生物學(xué)等相關(guān)學(xué)科的基礎(chǔ)知識(shí)貫穿其中。4分子藥理學(xué)（MolecularPharmacology)分藥物的作用機(jī)制ReceptorsDrug/receptorsandbiologicalresponsesSecond-messengersystemsThechemistryofdrug-receptorbindingDynamicsofdrug-receptorbindingDoseresponserelationshipPotencyandintrinsicactivityDrugantagonism5藥物的作用機(jī)制Receptors5ReceptorAfundamentalconceptofpharmacology:toinitiateaneffectinacell,mostdrugscombinewithsomemolecularstructureonthesurfaceoforwithinthecell.Thismolecularstructureiscalledareceptor.Receptor+Drug?Complex???

Responses6ReceptorAfundamentalconceptDRUGRECEPTORSANDBIOLOGICAL

RESPONSESReceptor:molecularsubstancesormacromoleculesintissuesthatcombinechemicallywiththedrug.Achreceptor→Nainflux→actionpotential→increasedfreeCa→contractionSpecificreceptivesubstancesserveastriggersofcellularreactions.7DRUGRECEPTORSANDBIOLOGICAL

AgonistvsAntagonistChemicalsthatinteractwithareceptortoinitiateacellularreactionaretermedagonists.Antagonistinteractswiththereceptorandpreventstheinteractionofagonistwithitsreceptor.8AgonistvsAntagonistChemicalsSECOND-MESSENGERSYSTEMSManyreceptorsarecapableofinitiatingachainofeventsinvolvingsecondmessengers.Gproteins,shortforguaninenucleotide–bindingproteins.Gproteinshavethecapacitytobindguanosinetriphosphate(GTP)andhydrolyzeittoguanosinediphosphate(GDP).Receptoractivation,Gprotein,adenylylcyclase,ATP-cAMP,kinasesactivation,proteinphosphorylation.?WhichGproteincoupleswiththereceptor?Whichkinaseisactivated?Whichproteinsareaccessibleforthekinasetophosphorylate9SECOND-MESSENGERSYSTEMSManyrThespecificbindingsitesforagonistsoccurattheextracellularsurface,whiletheinteractionwithGproteinsoccurswiththeintracellularportionsofthereceptor.Thegeneraltermforanychainofeventsinitiatedbyreceptoractivationissignaltransduction.10Thespecificbindingsitesfor1111THECHEMISTRYOFDRUG–RECEPTOR

BINDINGcovalentbond:irreversibleCovalentbondformationisadesirablefeatureofanantineoplasticorantibioticdrugionicbondresultsfromtheelectrostaticattractionthatoccursbetweenoppositelychargedions.hydrogenbond&VanderWaalsbondsstructure–activityrelationships12THECHEMISTRYOFDRUG–RECEPTORDYNAMICSOFDRUG–RECEPTOR

BINDINGtheelectrostaticattractionoftheionicisthefirstforcethatdrawstheionizedmoleculetowardtheoppositelychargedreceptorsurface.ionicbondmustbereinforcedbyahydrogenorvanderWaalsbondorbothbeforesignificantreceptoractivationcanoccur.Thebetterthestructuralfitbetweendruganditsreceptor,themoresecondary(i.e.,hydrogenandvanderWaals)bondscanform.Continualrandomassociationanddissociation13DYNAMICSOFDRUG–RECEPTOR

BINDDOSE–RESPONSERELATIONSHIPTherelationshipbetweenthe[drug]andthebiologicaleffectitproduces.14DOSE–RESPONSERELATIONSHIPTheQuantalRelationshipsDose(plottedonthehorizontalaxis)isevaluatedagainstthepercentageofanimalsintheexperimentalpopulationthatisprotectedbyeachdose(verticalaxis).Thesigmoidshapeisacharacteristicofmostdose–responsecurveswhenthedoseisplottedonageometric,orlogscale.15QuantalRelationshipsDose(ploTherapeuticIndexEffectiveDoseED50(effectivedose,50%;i.e.,thedosethatwouldprotect50%oftheanimals).LethalDosepercentofanimalskilledbyphenobarbitalagainstdoseLD50/ED50;thisisthetherapeuticindex.LD1/ED99:comparisonofthelowestdosethatproducestoxicity(e.g.,LD1)andthehighestdosethatproducesamaximaltherapeuticresponse(e.g.,ED99).16TherapeuticIndexEffectiveDosProtectiveIndexUsually,undesirablesideeffectsoccurindoseslowerthanthelethaldoses.Forexample,phenobarbitalinducesdrowsinessandanassociatedtemporaryneurologicalimpairment.Sinceanticonvulsantdrugsareintendedtoallowpeoplewithepilepsytolivenormalseizure-freelives,sedationisnotacceptable.Thus,animportantmeasureofsafetyforananticonvulsantwouldbetheratioED50(neurologicalimpairment)/ED50(seizureprotection).Thisratioiscalledaprotectiveindex.17ProtectiveIndexUsually,undesPotencyandIntrinsicActivityDrugsaandbproducethesamemaximumresponse.Drugaismorepotent,thatis,lessofdrugaisneededtoproduceagivenresponse.Drugchaslessmaximumeffectthaneitherdrugaordrugb.Drugcissaidtohavealowerintrinsicactivitythantheothertwo.18PotencyandIntrinsicActivityDRUGANTAGONISMChemicalAntagonism:Chemicalantagonisminvolvesadirectchemicalinteractionbetweentheagonistandantagonist.FunctionalAntagonism:Functionalantagonismisatermusedtorepresenttheinteractionoftwoagoniststhatactindependentlyofeachotherbuthappentocauseoppositeeffects.CompetitiveAntagonism:Competitiveantagonismisthemostfrequentlyencounteredtypeofdrugantagonisminclinicalpractice.Theantagonistcombineswiththesamesiteonthereceptorasdoestheagonist,butunliketheagonist,doesnotinducearesponse;thatis,theantagonisthaslittleornoefficacy.19DRUGANTAGONISMChemicalAntagoEquilibriumvsnon-equilibiurm20Equilibriumvsnon-equilibiurNoncompetitiveAntagonism21NoncompetitiveAntagonism21分子藥理學(xué)22分子藥理學(xué)1教學(xué)大綱中文名稱分子藥理學(xué)英文名稱MolecularPharmacology

課內(nèi)總學(xué)時(shí)：32教學(xué)方式：講授撰寫人：晏為力考核方式：考試+論文報(bào)告開(kāi)課學(xué)期：

Ⅰ學(xué)分?jǐn)?shù):2內(nèi)容偏重：理論

教學(xué)要求及目的

１．使學(xué)生了解分子藥理學(xué)的基礎(chǔ)知識(shí)和各系統(tǒng)分子藥理學(xué)的進(jìn)展，為從事藥學(xué)基礎(chǔ)研究工作和新藥開(kāi)發(fā)奠定理論基礎(chǔ)。23教學(xué)大綱中文名稱分子藥理學(xué)2課程內(nèi)容內(nèi)容

授課人

日期1．緒論:分子藥理學(xué)研究?jī)?nèi)容,藥物作用的機(jī)制

晏為力9/112．受體藥理及信號(hào)傳導(dǎo)

9/183．細(xì)胞內(nèi)第二信使蛋白激酶及有關(guān)藥物進(jìn)展

9/254．炎癥介質(zhì)與抗炎藥物

10/9

5．抗糖尿病藥物

譚睿10/166．缺血再灌注性損傷的分子機(jī)制

10/23

7．抗體及生物技術(shù)藥物分子藥理學(xué)基礎(chǔ)

喻凱10/308．離子通道和抗心律失常藥理

11/69．高血壓藥的分子藥理學(xué)

11/1310．細(xì)胞色素p450及調(diào)控

11/20

11．神經(jīng)藥理的分子藥理學(xué)基礎(chǔ)

黃新河

11/2712．學(xué)習(xí)、記憶藥理及老年癡呆的藥物干預(yù)

12/413．細(xì)胞凋亡機(jī)理及抗癌藥物研究進(jìn)展

12/1114．氧自由基與抗氧化劑及一氧化氮

12/18

考核方式：

上課情況15%，學(xué)期論文25%，考試60%24課程內(nèi)容內(nèi)容分子藥理學(xué)（MolecularPharmacology)分子藥理學(xué)屬于一門新興學(xué)科，其與傳統(tǒng)藥理學(xué)的最大區(qū)別就在于，它是從分子水平和基因表達(dá)的角度去闡釋藥物作用及其機(jī)制。Theuseoftechniquesofmolecularbiologytoenhancetheunderstandingofthemechanismofactionofexistingdrugs,andwiththehelpofmoleculargraphicstopredictthestructureofnoveldrugs,especiallycompoundsthatmightbindtoproteinsofknownstructure.近代藥理學(xué)的進(jìn)展，主要表現(xiàn)在受體理論、離子通道、信息傳遞、細(xì)胞因子等分子水平上的研究突破。分子藥理學(xué)是指其學(xué)科層次、水平上的科學(xué)性和先進(jìn)性達(dá)到“分子水平”，且又屬于“藥理學(xué)”范疇，分子生物學(xué)等相關(guān)學(xué)科的基礎(chǔ)知識(shí)貫穿其中。25分子藥理學(xué)（MolecularPharmacology)分藥物的作用機(jī)制ReceptorsDrug/receptorsandbiologicalresponsesSecond-messengersystemsThechemistryofdrug-receptorbindingDynamicsofdrug-receptorbindingDoseresponserelationshipPotencyandintrinsicactivityDrugantagonism26藥物的作用機(jī)制Receptors5ReceptorAfundamentalconceptofpharmacology:toinitiateaneffectinacell,mostdrugscombinewithsomemolecularstructureonthesurfaceoforwithinthecell.Thismolecularstructureiscalledareceptor.Receptor+Drug?Complex???

Responses27ReceptorAfundamentalconceptDRUGRECEPTORSANDBIOLOGICAL

RESPONSESReceptor:molecularsubstancesormacromoleculesintissuesthatcombinechemicallywiththedrug.Achreceptor→Nainflux→actionpotential→increasedfreeCa→contractionSpecificreceptivesubstancesserveastriggersofcellularreactions.28DRUGRECEPTORSANDBIOLOGICAL

AgonistvsAntagonistChemicalsthatinteractwithareceptortoinitiateacellularreactionaretermedagonists.Antagonistinteractswiththereceptorandpreventstheinteractionofagonistwithitsreceptor.29AgonistvsAntagonistChemicalsSECOND-MESSENGERSYSTEMSManyreceptorsarecapableofinitiatingachainofeventsinvolvingsecondmessengers.Gproteins,shortforguaninenucleotide–bindingproteins.Gproteinshavethecapacitytobindguanosinetriphosphate(GTP)andhydrolyzeittoguanosinediphosphate(GDP).Receptoractivation,Gprotein,adenylylcyclase,ATP-cAMP,kinasesactivation,proteinphosphorylation.?WhichGproteincoupleswiththereceptor?Whichkinaseisactivated?Whichproteinsareaccessibleforthekinasetophosphorylate30SECOND-MESSENGERSYSTEMSManyrThespecificbindingsitesforagonistsoccurattheextracellularsurface,whiletheinteractionwithGproteinsoccurswiththeintracellularportionsofthereceptor.Thegeneraltermforanychainofeventsinitiatedbyreceptoractivationissignaltransduction.31Thespecificbindingsitesfor3211THECHEMISTRYOFDRUG–RECEPTOR

BINDINGcovalentbond:irreversibleCovalentbondformationisadesirablefeatureofanantineoplasticorantibioticdrugionicbondresultsfromtheelectrostaticattractionthatoccursbetweenoppositelychargedions.hydrogenbond&VanderWaalsbondsstructure–activityrelationships33THECHEMISTRYOFDRUG–RECEPTORDYNAMICSOFDRUG–RECEPTOR

BINDINGtheelectrostaticattractionoftheionicisthefirstforcethatdrawstheionizedmoleculetowardtheoppositelychargedreceptorsurface.ionicbondmustbereinforcedbyahydrogenorvanderWaalsbondorbothbeforesignificantreceptoractivationcanoccur.Thebetterthestructuralfitbetweendruganditsreceptor,themoresecondary(i.e.,hydrogenandvanderWaals)bondscanform.Continualrandomassociationanddissociation34DYNAMICSOFDRUG–RECEPTOR

BINDDOSE–RESPONSERELATIONSHIPTherelationshipbetweenthe[drug]andthebiologicaleffectitproduces.35DOSE–RESPONSERELATIONSHIPTheQuantalRelationshipsDose(plottedonthehorizontalaxis)isevaluatedagainstthepercentageofanimalsintheexperimentalpopulationthatisprotectedbyeachdose(verticalaxis).Thesigmoidshapeisacharacteristicofmostdose–responsecurveswhenthedoseisplottedonageometric,orlogscale.36QuantalRelationshipsDose(ploTherapeuticIndexEffectiveDoseED50(effectivedose,50%;i.e.,thedosethatwouldprotect50%oftheanimals).LethalDosepercentofanimalskilledbyphenobarbitalagainstdoseLD50/ED50;thisisthetherapeuticindex.LD1/ED99:comparisonofthelowestdosethatproducestoxicity(e.g.,LD1)andthehighestdosethatproducesamaximaltherapeuticresponse(e.g.,ED99).37TherapeuticIndexEffectiveDosProtectiveIndexUsually,undesirablesideeffectsoccurindoseslowerthanthele