cholinergic antagonists medicinal chemistry

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Cholinergic Antagonist

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  • 1. Cholinergic antagonistsMedicinal ChemistrySrikanth Kolluru, Ph.D.Rm: 320kolluru@pharmacy.tamhsc.edu361-593-3034
  • 2. Lecture outline Introduction Muscarinic antagonists Therapeutic application Structure Activity Relationship (SAR) studies Specific muscarinic antagonists Nicotinic antagonists Introduction Discovery Different classes of nicotinic antagonists
  • 3. Learning objectivesAftercompletionofthistopicstudentsshouldbeableto1. Identifythestructuresanddiscusstherapeuticusesofvarious classesmuscarinicandnicotinicantagonists2. Identifyacetylcholinebindingresiduesatthemuscarinicreceptor3. Discussstructureactivity/pharmacokineticrelationshipsof antimuscarinicsincluding 1. Substitutionatalphacarbonwithrespecttoestergroup 2. Substitutiononthenitrogen4. Identifychemicalclassofanymuscarinicantagonist5. Identifythemetabolites(active/inactive)ofspecific antimuscarinics6. Identifythestructuralrequirementsofacompoundtobea neuromuscularblocker7. Discusshownicotinicantagonistsbindatthereceptorsite8. Compareandcontrastdepolarizingandnondepolarizing neuromuscularblockers9. Identifythemetabolitesof(activeandinactive)ofsteroidand tetrahydroisoquinolinetypeneuromuscularblockers
  • 4. Cholinergics ACh
  • 5. What is muscarinic antagonist ? An agent that have high binding affinity for the muscarinic receptor but have no intrinsic activity. What are they competing with to occupy muscarinic receptor? Acetylcholine They are competitive (reversible) antagonists of acetylcholine Their pharmacological actions are opposite to that of the muscarinic agonists
  • 6. Muscarinic Antagonists Drugs which bind to cholinergic receptor but do not activate it Prevent acetylcholine from binding Opposite clinical effect to agonists - lower activity of acetylcholine Postsynaptic Postsynaptic nerve nerve Ach Ach AchAntagonist
  • 7. Muscarinic Antagonists Clinical Effects Decrease of saliva and gastric secretions Relaxation of smooth muscle Decrease in motility of GIT and urinary tract Dilation of pupils Uses Shutting down digestion for surgery Ophthalmic examinations Relief of peptic ulcers Treatment of Parkinsons Disease Anticholinesterase poisoning Motion sickness
  • 8. Muscarinic antagonists arecommonly referred to as Anticholinergics Antimuscarinics Cholinergic blockers Antispasmodics Parasypatholytics
  • 9. What are the therapeutic applications of antimuscarinics? M-Receptor Antimuscarinic Therapeutic Organ Effect effect indicationEye Iris circular muscle Contracts Relaxes Ciliary muscle Contracts Relaxes MydriaticHeart Sinoatrial node Decelerates Accelerates Bradycardia Atrial contractility Decelerates Accelerates Bradycardia AsthmaBronchiole smooth muscle Contracts Relaxes Allergic rhinitisGastrointestinal tract Smooth muscle Contracts Relaxes GI antispasmodic Secretions Increases Decreases Sphincters Relaxes Contracts OveractiveBladder smooth muscles Contracts Relaxes bladder
  • 10. Binding site (muscarinic) hydrophobic pocket Trp-307 Asp311 CH3 CH3 CO 2 N CH3 hydrophobic O O pockets CH3 Trp-616 Trp-613 H H O N hydrophobic pocket Asn-617
  • 11. Binding site (muscarinic) vdw Trp-307 Asp311 CH3 CH3 CO 2 Ionic bond N CH3 vdw O O H-bonds CH3 vdw Trp-616 Trp-613 H H O N Asn-617 It is postulated that muscarinic antagonists bind to the Asp and contain hydrophobic substituents that bind to a hydrophobic pocket in the receptor, which does not allow the change in conformation needed to transfer the agonist signal to the coupled G protein
  • 12. Structure Activity Relationship(SAR) Studies Acetylcholine (ACH)Acetyl CH3 group is substituted with atleast one phenyl ring for antimuscarinic activity Acetylcholine analogue antimuscarinics
  • 13. Substitutions at -carbon with respect to ester group1. Maybeahydrogenatom,ahydroxyl group,ahydroxymethyl group,ora carboxamide2. Hydroxylgrouporahydroxymethyl group, theantagonistusuallyismorepotentR2 andR3 shouldbecarbocyclic orheterocyclicrings(phenyl,cyclohexyl,cyclopentyl)formaximalantagonistpotency SubstitutionofnaphthaleneringsatR2 andR3 affordsinactivecompounds, becauseofsteric hindranceatthemuscarinic receptor. BiggerR2 andR3groupsbindtothehydrophobicregionoutsidetheAch receptorsite ThehydroxylgroupatR1 presumablyincreasesbindingstrengthbyparticipating inahydrogenbondinteractionatthereceptor.
  • 14. Changes at ester groupThis substituent may also be anether oxygen, or it may be absentcompletely. Ester group provides most potent anticholinergic activity
  • 15. Substitution at the amine groupCompounds possessing the quaternary Quaternaryammoniumcompoundsammonium group exhibit nicotinic possessmostpotentanticholinergicantagonist activity at high doses. activity Methyl, ethyl, propyl, or isopropyl groups are toleratedTertiary amines also possess antagonist activity, presumably by binding to thereceptor in the protonated form.Quaternary ammonium drugs are primarily used in the treatment of ulcers orother conditions for which a reduction in gastric secretions and reducedmotility of the gastrointestinal tract are desired
  • 16. Changes at R4 position Optimumchainlengthis24carbons. Twocarbonchainpossessthemost antagonisticac