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19 Cards in this Set
- Front
- Back
What is the role of the kidney in the RAS?
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Kidney -> Pro-renin (peptide) -> Renin (protease)
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What catalyzes the conversion of Pro-renin to Renin?
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Cathepsin B
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What is the R.L.S. in the RAS?
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Angiotensinogen -> Angiotensin I cataylzed by Renin
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What is the role of chymase?
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Alternative, Non-ACE ANGII generating pathways
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What is the substrate for ACE?
What is the chemistry catalyzed by the enzyme? What is the product of enzyme cleavage? |
Angiotensin I (a decapeptide)
Peptide Cleavage Angiotensin II (a hexapeptide) |
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What is the correlation between ACE and bradykinin?
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ACE catalyzes the degradation of bradykinin (a stimulator of biosynthesis of endogenous vasodilators) to inactive fragments.
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What 4 pieces of additional information should be known about ACE?
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1)Limited substrate specificity (doesn't accept all decapeptides)
**REQUIRED - carboxylate anion to be present in substrate** 2)CArboxydipeptidase-cleaves starting at carboxy terminus 2 amino acids at a time 3)Exopeptidase-cleaves at the terminus of a peptide 4)Metalloprotease-contains a critical Zn++ ion in each active site |
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SAR of ACE Inhibitors
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1)N-ring must contain COOH to mimic C-terminal carboxylate
2)A sulfahydryl group, carboxylate, or phosphinate can serve as Zn++ binding groups 3)Binding of Zn++ through either a carboxylate or phosphinate mimics peptide hydrolysis transition state 4)Large hydrophobic heterocyclic rings in the the N-ring increase potency and alter pharmaokinetic parameters |
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What should be known about sulfhydryl containing ACE inhibitors and compounds?
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They produce high incidence of skin rash and taste disturbances
Can form disulfides which may shorten duration of action Sulfhydryl group shows superior binding to zinc |
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What is a complication associated with ACE inhibitors?
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Non-productive cough (need to treat with a narcotic)
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What are the two active sites proposed to be present in ACE?
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Angiotensin I and Bradykinin
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How more endogenous substrates are there for ACE?
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More than 1
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What is a site selective inhibitor?
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Inhibits only the conversion of ATI to ATII
No binding of these agents to bradykinin-related ACE active site |
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What is the good and bad news of a site selective inhibitor?
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Good = No cough
Bad = Decreased effect due to absence of vasodilation component of mechanism |
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What is the chymase inhibitor?
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CP-162,213
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ATII receptors subtype AT1:
What is its location? What type of receptor is it? What is its 2nd messenger? What are the 4 physiological effects of receptor activation upon binding of ATII? |
1)Aorta, Liver, Adrenal Gland
2)G-protein coupled receptor-7 transmembrane domains 3)Phosphoinositol 4)a-Vasoconstriction b-Aldosterone release c-Catecholamine release d-renal Na+ reabsorption |
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ATII receptors subtype AT2:
What is its location? What type of receptor is it? What is its 2nd messenger? What are the 4 physiological effects of receptor activation upon binding of ATII? |
1)Adrenal gland, uterus, brain
2)Several subtypes of AT2 binding site 3)None identified 4)a-renal function b-Restinosis c-Growth d-wound healing |
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SAR for non-peptide based AT1 selective receptor antagonists
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1)Position #1: Called "variable region"
-Biphenyl substituent or aromatic heterocycle can take the place of one of the phenyl rings -In ortho position, there must be an acidic functional group (COOH, Sulfonamide, Tetrazole) 2)Position #2-"hydrocarbon region" -3-4 carbons optimal, branching is bad, double bond is Okay 3)Position#3-Scaffolding ONLY-no interaction with the receptor 4)Position#4-EWG -lipophilic in character -I>Cl>Br -F is Okay 5)Position#5-H-bonding region -small and must be H-bond acceptor (COOH, CH2OH) |
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How do you increase potency in an AT1 selective receptor antagonist if the H-bonding region in postion #5 has the substituent CH2OH?
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Oxidation due CO2H
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