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19 Cards in this Set

  • Front
  • Back
What is the role of the kidney in the RAS?
Kidney -> Pro-renin (peptide) -> Renin (protease)
What catalyzes the conversion of Pro-renin to Renin?
Cathepsin B
What is the R.L.S. in the RAS?
Angiotensinogen -> Angiotensin I cataylzed by Renin
What is the role of chymase?
Alternative, Non-ACE ANGII generating pathways
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)
What is the correlation between ACE and bradykinin?
ACE catalyzes the degradation of bradykinin (a stimulator of biosynthesis of endogenous vasodilators) to inactive fragments.
What 4 pieces of additional information should be known about ACE?
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
SAR of ACE Inhibitors
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
What should be known about sulfhydryl containing ACE inhibitors and compounds?
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
What is a complication associated with ACE inhibitors?
Non-productive cough (need to treat with a narcotic)
What are the two active sites proposed to be present in ACE?
Angiotensin I and Bradykinin
How more endogenous substrates are there for ACE?
More than 1
What is a site selective inhibitor?
Inhibits only the conversion of ATI to ATII

No binding of these agents to bradykinin-related ACE active site
What is the good and bad news of a site selective inhibitor?
Good = No cough

Bad = Decreased effect due to absence of vasodilation component of mechanism
What is the chymase inhibitor?
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
b-Aldosterone release
c-Catecholamine release
d-renal Na+ reabsorption
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
d-wound healing
SAR for non-peptide based AT1 selective receptor antagonists
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
-lipophilic in character
-F is Okay
5)Position#5-H-bonding region
-small and must be H-bond acceptor (COOH, CH2OH)
How do you increase potency in an AT1 selective receptor antagonist if the H-bonding region in postion #5 has the substituent CH2OH?
Oxidation due CO2H