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all mAChR's are activated by:
ACh
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all mAChR's are blocked by:
atropine
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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
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which group is required in cholinergic agonists?
quaternary ammonium group (far right)
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which group is susceptible to rapid hydrolysis?
acyloxy group/ester (far left) by cholinesterase
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in cholinergic agonists, for maximum potency, the size of the alkyl groups should...
not exceed the size of a methyl group
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in cholinergic agonists, there should be a ___ unit between oxygen & nitrogen
two-carbon
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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)
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carbamate ester analog of ACh that is more resistant toward acid-, base-, or enzyme-catalyzed hydrolysis
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carbamate analog of methacholine used to stimulate GI tract & bladder after surgery
- bethanechol chloride (urecholine)
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purpose of replacing the methyl group with NH2 in ACh
acts as bioisostere, making it more resistant to hydrolysis
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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
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identify this cholinergic agonist used to treat glaucoma that does not adhere to traditional SAR (inactive after hydrolysis or epimerization):
pilocarpine
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purpose of ethylene bridge group:
prevents hydrolysis of O bond
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what can occur from exposure to insecticides or nerve gases?
AChE poisoning
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inhibit rapid hydrolysis of ACh to increase the concentration of ACh in the synapse, resulting in the production of both muscarinic & nicotinic effects
anticholinesterases
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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
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aryl carbamate AChEI that binds to AChE & forms a carbamylated enzyme
physostigmine
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identify this AChEI used to treat glaucoma:
physostigmine
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which part of neostigmine prevents hydrolysis of the ester?
aromatic
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which molecule lacks CNS activity? why?
pyrimidostigmine - incorporated charged nitrogen into pyridine ring makes it less lipophilic
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what are these used as a therapy for?
myesthenia gravis
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substrates for AChE that result in an acylated enzyme more stable to hydrolysis than a carboxylate ester
irreversible AChEI's (eg: phosphate esters)
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important difference between irreversible phosphoester-derived AChEIs and reversible AChEIs is that phosphorylated AChE can undergo a process known as...
aging
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result of cleavage of one or more of the phosphoester bonds while AChE is phosphorylated
aging
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irreversible AChEIs are used in the treatment of what diseases? (2)
- 1) glaucoma
- 2) insecticides
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act as competitive (reversible) antagonists of ACh (also referred to as anticholinergics)
muscarinic antagonists
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therapeutic value of muscarinic antagonists (anticholinergics)
treat SM spasms associated w/ increased tone of GI tract, opthalmologic exams, gastric ulcers, cold/flu
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name 2 alkaloid muscarinic antagonists
- 1) atropine
- 2) scopolamine
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identify this muscarinic antagonist:
atropine
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what does the circled portion of this muscarinic antagonist resemble?
- ACh
- (molecule is atropine)
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for maximal antagonist potency, R1 & R2 should be...
carbocyclic or heterocyclic
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