1. MedicinalChemistry SrikanthKolluru,Ph.D.Rm:320;Ph.No:3615933034,kolluru@pharmacy.tamhsc.edu

2. Lecture overview Reviewofconcepts Acetylcholinemimetics(muscarinicagonists) Biosynthesisandmetabolismofacetylcholine SAR(StructureActivityRelationship)studies Variousmuscarinicagonists Acetylcholinesteraseinhibitors(Anticholinesterases) Mechanismofacetylcholineesterasehydrolysis Reversibleandirreversibleinhibitorsofacetylocholineesterase Antidotesforirreversibleinhibitorsofacetylcholine 3. Learning objectives Aftercompletingthistopicstudentsshouldbeableto1. Discussbiosynthesisandmetabolismofacetylcholine(ACh)2. Discussmuscarinicandnicotinicreceptorssubtypes,tissuelocationand theirfunction3. IdentifypropertiesofAChwhichlimitsitsuseastherapeuticagent4. IdentifyaminoacidresidueswhichinteractswithAChatmuscarinicas wellasAChE catalyticsite5. Discussstructuralfeaturesthataffectsactivityofmuscarinicagonists1. Substitutiononnitrogen2. Substitutiononethylenebridgeandstereochemistryassociatedwithit3. Changesontheacyloxygroup6. Identifytherapeuticusesandmetabolitesofmuscarinicagonists7. Identifythehydrolysisproductsofacetylcholineandvarious acetylcholineesteraseinhibitors8. Discussthesite/mechanismofactionofirreversibleAChEIs9. Identifytheimportantfunctionalgroupswhichserveasabasisinthe designofAChEIs10.DiscussmechanismbywhichPralidoximechloride(2PAM)actsas antidoteforirreversibleAChEIs. 4. Useful Resources Actionpotentialhttp://www.youtube.com/watch?v=SCasruJTDU&NR=1 Synaptictransmissionofnerveimpulse.http://www.youtube.com/watch?v=HXx9qlJetSU http://video.search.yahoo.com/video/play?p=agonists+and+antagonists&ei=UTF8&fr=slv8msgr&fr2=tabweb&tnr=21&vid=000125901594RequiredReading: Foyes PrinciplesofMedicinalChemistry,6th Edition,Chapter12Additionalreference: AnIntroductiontoMedicinalChemistry,FourthEditionbyGrahamL.Patrick;OxfordUniversityPress:ISBN:9780199234479 5. Review Nervoussystem Central Peripheral Somatic Autonomous Sympathetic Parasympathetic Enteric Neurotransmitters Acetylcholine Epinephrine Norepinephrine Cholinergicreceptors Muscarinicreceptors Nicotinicreceptors 6. Nerve TransmissionPeripheral nervous system Skeletal muscleCNS(Somatic)Ach(N) CNS (Autonomic)Synapse Ach (N)NASympathetic AdrenalineAchAdrenal(N)medullaAUTONOMICParasympathetic SynapseAchAch (M)(N)Smooth muscleCardiac muscle 7. Adrenergic and cholinergicinnervations in sympathetic andparasympathetic nervous systems 8. NeurotransmissionActionpotentialhttp://www.youtube.com/watch?v=U0NpTdge3aw&feature=relatedSynaptictransmissionofnerveimpulse.http://www.youtube.com/watch?v=HXx9qlJetSU 9. Nerve TransmissionSynapses100-500A ReceptorsNerve impulse New signalNerve NerveVesicles containing Release ofReceptor bindingneurotransmitters neurotransmitters and new signal 10. NeurotransmitterAcetylcholine (Ach) O + C NMe 3 H 3COAcetyl Choline 11. Transmission processSignal in nerve 1 Nerve 2Nerve 1.. . Signal... .... Acetylcholine Acetylcholinesterase enzymeVesicleCholinergic receptor 12. Transmission processVesicles fuse with membrane and release AchNerve 2Nerve 1 Signal 13. Transmission process Nerve 2 14. Transmission process Ach binds to the receptor 2o Message Induced fit triggers 2o message Triggers firing of nerve 2 Ach undergoes no reactionNerve 2 15. Transmission processAch departs receptorReceptor reverts to resting stateAch binds to acetylcholinesterase Nerve 2 16. Transmission processAch hydrolysedby acetylcholinesterase O O C C HO NMe3H 3CO H 3COH +NMe3 AcetylcholineAcetic acid Choline Nerve 2 17. Transmission processCholine binds to carrier proteinCholineNerve 2 Nerve 1Carrier protein for choline 18. Transmission processCholine transported into nerve Nerve 2 Nerve 1 19. Transmission process Ach resynthesizedNerve 2Nerve 1E 1 = Choline acetyltransferaseOOCC E1NMe3 H 3C SCoA + HO CH2 CH2 NMe3H 3COCholineAcetylcholine 20. Transmission processAch repackaged in vesicles Nerve 2 Nerve 1 21. Biosynthesis of acetylcholineSerine decarboxylaseSerine Ethanolamine CholineNmethylSAdenosyl transferasemethionineON(CH3)3 Cholineacetyl HO N(CH3)3H3C O transferaseAcetylcholine Choline 22. Metabolism of AcetylcholineAChESerOH + H2O + AChESerOH+ (inactive) 23. Cholinergic receptors Acetylcholine HO H(S)(R)N (S)(S) + N (CH3)3 Cl H3CO CH3 N ()MuscarineS()Nicotine1. Muscarinic receptors2. Nicotinic receptorsActivates cholinergic Activates cholinergicreceptors on smooth receptors at nerve synapsesmuscle and cardiac muscle and on skeletal muscle 24. Nerve TransmissionPeripheral nervous system Skeletal muscleCNS(Somatic)Ach(N) CNS (Autonomic)Synapse Ach (N)NASympathetic AdrenalineAchAdrenal(N)medullaAUTONOMICParasympathetic SynapseAchAch (M)(N)Smooth muscleCardiac muscle 25. Muscarinic receptor subtypes andfunctionsReceptor TissuelocationFunctionM1 CNS,gastricandsalivaryglands, Cogni vefunc on autonomicganglia,entericnervesSeizureac vity,Secre onsAutonomicgangliadepolariza onDAreleaseandlocomo onM2 Autonomicnerveterminals;CNS;heart;Smoothmusclecontrac on smoothmuscleNeuralinhibitioninperipheryviaautoreceptorsandheteroreceptorGanglionic transmissionNeuralinhibi oninCNS,HeartrateTremorshypothermia&analgesiaM3 CNS(