分子药理学课件

分子药理学1分子药理学1教学大纲中文名称分子药理学英文名称MolecularPharmacology

课内总学时：32教学方式：讲授撰写人：晏为力考核方式：考试+论文报告开课学期：

Ⅰ学分数:2内容偏重：理论

教学要求及目的

１．使学生了解分子药理学的基础知识和各系统分子药理学的进展，为从事药学基础研究工作和新药开发奠定理论基础。2教学大纲中文名称分子药理学2课程内容内容

授课人

日期1．绪论:分子药理学研究内容,药物作用的机制

晏为力9/112．受体药理及信号传导

9/183．细胞内第二信使蛋白激酶及有关药物进展

9/254．炎症介质与抗炎药物

10/9

5．抗糖尿病药物

谭睿10/166．缺血再灌注性损伤的分子机制

10/23

7．抗体及生物技术药物分子药理学基础

喻凯10/308．离子通道和抗心律失常药理

11/69．高血压药的分子药理学

11/1310．细胞色素p450及调控

11/20

11．神经药理的分子药理学基础

黄新河

11/2712．学习、记忆药理及老年痴呆的药物干预

12/413．细胞凋亡机理及抗癌药物研究进展

12/1114．氧自由基与抗氧化剂及一氧化氮

12/18

考核方式：

上课情况15%，学期论文25%，考试60%3课程内容内容分子药理学（MolecularPharmacology)分子药理学属于一门新兴学科，其与传统药理学的最大区别就在于，它是从分子水平和基因表达的角度去阐释药物作用及其机制。Theuseoftechniquesofmolecularbiologytoenhancetheunderstandingofthemechanismofactionofexistingdrugs,andwiththehelpofmoleculargraphicstopredictthestructureofnoveldrugs,especiallycompoundsthatmightbindtoproteinsofknownstructure.近代药理学的进展，主要表现在受体理论、离子通道、信息传递、细胞因子等分子水平上的研究突破。分子药理学是指其学科层次、水平上的科学性和先进性达到“分子水平”，且又属于“药理学”范畴，分子生物学等相关学科的基础知识贯穿其中。4分子药理学（MolecularPharmacology)分药物的作用机制ReceptorsDrug/receptorsandbiologicalresponsesSecond-messengersystemsThechemistryofdrug-receptorbindingDynamicsofdrug-receptorbindingDoseresponserelationshipPotencyandintrinsicactivityDrugantagonism5药物的作用机制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分子药理学22分子药理学1教学大纲中文名称分子药理学英文名称MolecularPharmacology

课内总学时：32教学方式：讲授撰写人：晏为力考核方式：考试+论文报告开课学期：

Ⅰ学分数:2内容偏重：理论

教学要求及目的

１．使学生了解分子药理学的基础知识和各系统分子药理学的进展，为从事药学基础研究工作和新药开发奠定理论基础。23教学大纲中文名称分子药理学2课程内容内容

授课人

日期1．绪论:分子药理学研究内容,药物作用的机制

晏为力9/112．受体药理及信号传导

9/183．细胞内第二信使蛋白激酶及有关药物进展

9/254．炎症介质与抗炎药物

10/9

5．抗糖尿病药物

谭睿10/166．缺血再灌注性损伤的分子机制

10/23

7．抗体及生物技术药物分子药理学基础

喻凯10/308．离子通道和抗心律失常药理

11/69．高血压药的分子药理学

11/1310．细胞色素p450及调控

11/20

11．神经药理的分子药理学基础

黄新河

11/2712．学习、记忆药理及老年痴呆的药物干预

12/413．细胞凋亡机理及抗癌药物研究进展

12/1114．氧自由基与抗氧化剂及一氧化氮

12/18

考核方式：

上课情况15%，学期论文25%，考试60%24课程内容内容分子药理学（MolecularPharmacology)分子药理学属于一门新兴学科，其与传统药理学的最大区别就在于，它是从分子水平和基因表达的角度去阐释药物作用及其机制。Theuseoftechniquesofmolecularbiologytoenhancetheunderstandingofthemechanismofactionofexistingdrugs,andwiththehelpofmoleculargraphicstopredictthestructureofnoveldrugs,especiallycompoundsthatmightbindtoproteinsofknownstructure.近代药理学的进展，主要表现在受体理论、离子通道、信息传递、细胞因子等分子水平上的研究突破。分子药理学是指其学科层次、水平上的科学性和先进性达到“分子水平”，且又属于“药理学”范畴，分子生物学等相关学科的基础知识贯穿其中。25分子药理学（MolecularPharmacology)分药物的作用机制ReceptorsDrug/receptorsandbiologicalresponsesSecond-messengersystemsThechemistryofdrug-receptorbindingDynamicsofdrug-receptorbindingDoseresponserelationshipPotencyandintrinsicactivityDrugantagonism26药物的作用机制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