Med Chem Exam 3

Question 1

AA to PGG2

Answer 1

Step 1 (COX site): COX enzymes uses 2 oxygens to form an endoperoxide and hydroperoxide

Question 2

PGG2 to PGH2

Answer 2

Hydroperoxidase reduces hydroperoxide from OOH to OH

Question 3

COX1

Answer 3

expressed in most cells and constantly makes PGs. Help with housekeeping like making bicarbonates and mucous in the stomach.

Question 4

COX2

Answer 4

forms PGs for inflammation. Much larger binding site (Ile vs Val in Cox 1)

Question 5

Prostacyclin

Answer 5

potent hypotensive agent and inhibits platelet aggregation

Question 6

TXA2

Answer 6

a potent vasoconstrictor and causes platelet aggregation, comes from PGH2 catalyzed by COX 1

(When COX 2 is inhibited, AA goes through COX 1 only, forms abundance of TxA2 and causes platelet aggregation)

Question 7

Montelukast

Answer 7

antagonists of CysLT1 receptors

Question 8

Dinoprostone

Answer 8

PGE2) – induces labor

Question 9

Misoprostol

Answer 9

(PGE1) – 15-OH moved to carbon 16, tertiary alcohol is difficult to get oxidized and its half-life is lengthened, EP3 agonist protects stomach lining from gastric acid by causing mucus and bicarbonate to be made from epithelial cells and reduction of acid in parietal cells

Question 10

Latanoprost

Answer 10

(PGF2) – Lipphilic prodrug, hydrolyzed by esterases, causes outflow of aqueous humor

Question 11

Salicylic acid

Answer 11

– irritating to GI, used as keratolytic on skin to remove warts and calluses

Question 12

Aspirin

Answer 12

• Aspirin acts on COX 1 and 2 through acetylating Ser-530 in the active site, this blocks the active site and prevents AA from interacting with Tyr-385
  o COX-1 - COX and POX inhibited
  o COX-2 – ONLY inhibits COX, POX is still normal and interacts with AA to form lipoxins (this is known as aspirin triggered lipoxin formation), lipoxins are anti-inflammatory

Question 13

Iloprost

Answer 13

enol oxygen atom replaced with carbon atom to increase half-life to 20-30 minutes, given by inhalation

Question 14

Olsalazine

Answer 14

prodrug, used to treat ulcerative colitis and inflammatory bowel diseases, has an azo-link so prodrug is not absorbed in GI tract but instead broken down by bacteria in the colon where inflammatory bowel disease is typically found

Question 15

Indomethacin

Answer 15

pseudo irreversible COX inhibitor, methyl group fits into small hydrophobic pocket of the enzyme to delay disassociation which is known as a “pseudo irreversible effect”

Question 16

Ibuprofen

Answer 16

non-selective inhibitor of COX, chiral center is present, sold as a racemic mixture, S enantiomer is is active and R enantiomer is inactive but gets converted in the body to the S version

Question 17

Naproxen

Answer 17

slow in inhibiting COX enzymes, more potent than aspirin and ibuprofen, long duration of action allows for twice daily dosing

Question 18

Coxibs

Answer 18

COX-2 selective NSAIDs, developed to fit in the COX-2 pocket which contains valine, COX-2 specificity to avoid GI irritation/damage, involved in blocking prostacyclin which acts as vasodilators and platelet aggregate inhibitors

Question 19

APAP

Answer 19

ONLY able to inhibit COX under two conditions: low AA levels and low peroxide levels, typically the heme forms a free radical with Tyr-385 to be used in the POX site, acetaminophen mimics this tyrosine to accept the free radical and inhibits enzyme activity.
- In an inflammatory state there are higher AA levels and more oxidative stress which causes acetaminophen to be less useful
- Large amounts of acetaminophen will be metabolized by liver into N-acetylimidoquinone which can react with hepatic proteins which lead to hepatic necrosis

Question 20

H1 receptors

Answer 20

• H1 receptors located in smooth muscles, endothelial cells, and CNS
  o Contract bronchial and smooth muscles, Increase Ca2+ to cause contraction
  o Decrease appetite and increase wakefulness
  o Dilates resistance vessels, induces NO to cause vasodilation of smooth muscles (hypotensive effect) VERY QUICK ONSET
  o Increase capillary permeability, proteins and fluid can flow through which causes edema, stimulates nerve endings (itch and pain)
  o Diseases include rhinorrhea, bronchoconstriction, anaphylaxis, conjunctivitis, and skin rash

Question 21

H2 receptors

Answer 21

• H2 receptors in parietal cells of the stomach. Involved in gastric acid secretion, cardiac muscle, smooth muscle, and CNS
  o Parietal cells secrete gastric acid, dilate smooth muscle, SLOW ONSET

Question 22

H2 receptors

Answer 22

• H2 receptors in parietal cells of the stomach. Involved in gastric acid secretion, cardiac muscle, smooth muscle, and CNS
  o Parietal cells secrete gastric acid, dilate smooth muscle, SLOW ONSET

Question 23

Triple Response of Lewis

Answer 23

allergy test, histamine used as a control
o red spot due to vasodilation
o flare in redness of surrounding area
o elevation (wheal) due to edema