FEB TEST: mechanisms

Question 1

Glucocorticoids

–two main actions

Answer 1

Transactivation - increase metabolic effects
–via dimer interaction with coactivator protein and GSR of gene

Transrepression - block inflammation and immune response
–via dimer inhibition of AP-1 or NF-kB on gene

Question 2

What immune effects do glucocorticoids have?

Answer 2

1. Decrease release of cytokines in response to oxidative stress
2. Decrease # and function of WBCs
3. Increase lipoprotein which inhibits PLA2 to decrease prostaglandins and leukotrienes

Question 3

How do estrogens work?

Answer 3

• Bind cytoplasmic receptor
• Receptor dissociates from HSP
• Receptor translocates to nucleus and acts as TF
• Overall result is increased protein synthesis

Question 4

What structural aspects are important for the function of synthetic steroidal estrogens?

Answer 4

Hydroxyl at 3 - essential for activity
Hydroxyl at 17b - required for activity
Aromaticity in ring A - required

3 and 17b can be masked (ether and ester, respectively) - PRODRUGS

17a can be substituted with ethynyl - allows for oral admin

16 OH decreases activity

Question 5

What structural aspects are important for the function of synthetic non-steroidal estrogens?

Answer 5

Rigid core
OH group required for agonist
Another OH 10-12 angstroms apart enchance

Additional aromatic ring leads to antagonist activity

Amin substituted side chain leads to antagonist activity

Question 6

How does clomiphene work?

Answer 6

It blocks negative estradiol feedback and thus increases LH and FSH secretion
–this stimulates ovulation

Question 7

What do aromatase inhibitors do?

Answer 7

Block the biosynthesis of estrogens

Question 8

How do progesterones work?

Answer 8

• Bind cytoplasmic receptor
• Receptor dissociates from HSP
• Receptor translocates to nucleus and acts as TF
• Overall result is increased protein synthesis

Question 9

What structural aspects are important for progestin activity?

Answer 9

Ketone at 3 required
C-18 Me (or Et) required

6-Me enhances
19-H enhances

17a-ethynyl gives oral activity
17B-OH ester used in oral prep

Aromatic/amine substituents on ring C give ANTAGONISM

Question 10

How does Danazol work?

Answer 10

inhibits the surges of LH and FSH and suppresses overran function

causes of atrophy of endometrium