PHRD6925 MedChem Lecture 2 - Drugs affecting cholinergic neurotransmission

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PHRD6925 MedChem Lecture 2 - Drugs affecting cholinergic neurotransmission
2015-03-04 03:11:26

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  1. identify:
  2. all mAChR's are activated by:
  3. all mAChR's are blocked by:
  4. 4 reasons ACh is a poor therapeutic
    • 1) easily hydrolyzed in stomach
    • 2) easily hydrolyed in blood
    • 3) no selectivity between mus & nic R types
    • 4) no selectivity between different target organs
  5. which group is required in cholinergic agonists?
    quaternary ammonium group (far right)
  6. which group is susceptible to rapid hydrolysis?
    acyloxy group/ester (far left) by cholinesterase
  7. in cholinergic agonists, for maximum potency, the size of the alkyl groups should...
    not exceed the size of a methyl group
  8. in cholinergic agonists, there should be a ___ unit between oxygen & nitrogen
  9. types of chemical interactions bteween cholinergic agonist and mAChR's (3)
    • 1) van der waal's (methyl's)
    • 2) ionic (N)
    • 3) H-bonds (O's in ester)
  10. carbamate ester analog of ACh that is more resistant toward acid-, base-, or enzyme-catalyzed hydrolysis
    • carbachol chloride
  11. carbamate analog of methacholine used to stimulate GI tract & bladder after surgery
    • bethanechol chloride (urecholine)
  12. purpose of replacing the methyl group with NH2 in ACh
    acts as bioisostere, making it more resistant to hydrolysis
  13. 4 characteristics of carbachol
    • 1) more resistant to hydrolysis vs ACh
    • 2) weak anticholinesterase activity (prolongs duration of carbachol)
    • 3) acts at nAChR's (not good)
    • 4) erratic absorption
  14. identify this cholinergic agonist used to treat glaucoma that does not adhere to traditional SAR (inactive after hydrolysis or epimerization):
  15. purpose of ethylene bridge group:
    prevents hydrolysis of O bond
  16. what can occur from exposure to insecticides or nerve gases?
    AChE poisoning
  17. inhibit rapid hydrolysis of ACh to increase the concentration of ACh in the synapse, resulting in the production of both muscarinic & nicotinic effects
  18. MOA of reversible anticholinesterases
    react w/ AChE to form an acylated/carbamylated enzyme, or bind to AChE w/ greater affinity than ACh but do not react w/ enyzyme
  19. aryl carbamate AChEI that binds to AChE & forms a carbamylated enzyme
  20. identify this AChEI used to treat glaucoma:
  21. which part of neostigmine prevents hydrolysis of the ester?
  22. which molecule lacks CNS activity? why?
    pyrimidostigmine - incorporated charged nitrogen into pyridine ring makes it less lipophilic
  23. what are these used as a therapy for?
    myesthenia gravis
  24. substrates for AChE that result in an acylated enzyme more stable to hydrolysis than a carboxylate ester
    irreversible AChEI's (eg: phosphate esters)
  25. important difference between irreversible phosphoester-derived AChEIs and reversible AChEIs is that phosphorylated AChE can undergo a process known as...
  26. result of cleavage of one or more of the phosphoester bonds while AChE is phosphorylated
  27. irreversible AChEIs are used in the treatment of what diseases? (2)
    • 1) glaucoma
    • 2) insecticides
  28. act as competitive (reversible) antagonists of ACh (also referred to as anticholinergics)
    muscarinic antagonists
  29. therapeutic value of muscarinic antagonists (anticholinergics)
    treat SM spasms associated w/ increased tone of GI tract, opthalmologic exams, gastric ulcers, cold/flu
  30. name 2 alkaloid muscarinic antagonists
    • 1) atropine
    • 2) scopolamine
  31. identify this muscarinic antagonist:
  32. what does the circled portion of this muscarinic antagonist resemble?
    • ACh
    • (molecule is atropine)
  33. for maximal antagonist potency, R1 & R2 should be...
    carbocyclic or heterocyclic