Drug Targets: Nuclear Receptors

Question 1

Nuclear receptors found where?

Answer 1

In the cytoplasm

Question 2

Anything that binds to nuclear receptor must be lipid soluble. Why?

Answer 2

It has to cross the membrane and get into the cytoplasm before it can interact with the receptor

Question 3

Role of n-terminal variable domain

Answer 3

Regulate transcriptional activity

Question 4

Role of dna-binding domain (DBD)

Answer 4

Highly conserved; binds receptor to hormone response element in DNA by two zinc-containing regions

Question 5

Role of hinge region

Answer 5

Enables intracellular translocation to the nucleus

Question 6

Role of ligand-binding domain(LBD)

Answer 6

Moderately conserved; enables specific ligand binding; contains nuclear localisation sequence (NLS); also binds chaperone proteins and facilitates receptor dimerisation

Question 7

AF1 role

Answer 7

Can promote the binding of other cofactors to the genetic material to influence the effects of the ligand receptor complex

Question 8

AF2 role

Answer 8

May/may not be present
-Similar to AF1 - serves to promote binding of activating factors

Question 9

Endogenous ligand

Answer 9

A naturally occurring small molecule that elicits a conformational change in the nuclear receptor upon binding

Question 10

4 classes of nuclear receptors

Answer 10

2 major classes and 2 minor classes

Question 11

Without hinge region what happens?

Answer 11

No translocation = no receptor action
Hinge region promotes dimerisation of nuclear receptors

Question 12

What type of ligand binding are type 1 receptors? Location?

Answer 12

Homodimers
Location -cytosolic

Question 13

What type of ligand binding are type 2 receptors? Location?

Answer 13

Heterodimers often with RXR
Location- nuclear

Question 14

Endogenous ligand for oestrogen receptor?

Answer 14

Sex hormone oestrogen

Question 15

Mechanism of action for oestrogen

Answer 15

• Bind to its receptor (oestrogen) in the cytoplasm
• in cytoplasm you get dimerisation and couple of activation factors
• receptor and ligand complex move to the nucleus where it will bind to destrogen response element on the DNA
• activation factors stimulate the action of the co-activators= form linkage of receptor with RNA polymerase (role-regulate transcription of genetic material)
• get significant effects upon cellular function

Question 16

Overactivity of the oestrogen receptor in breast tissue can lead to?
example of drug treatment

Answer 16

Forms of breast cancer
Drug-tamoxifen, fulvestrant

Question 17

Tamoxifen leads to? Fully activated transcription or partially activated transcription or no transcription

Answer 17

Partially activated transcription

Question 18

Fulvestrant leads to? Fully activated transcription or partially activated transcription or no transcription

Answer 18

No transcription

Question 19

Oestradiol leads to? Fully activated transcription or partially activated transcription or no transcription

Answer 19

Fully activated transcription

Question 20

Mechanism of action for tamoxifen

Answer 20

• Binds to oestrogen receptor and will act to modulate the function of the receptor (still get dimerisation and translocation in nucleus)
  -Activation factor = only one activation factor, before had couple of coactivators (AF1 active, AF2 inactive)
  -Results in partially activated transcription

Question 21

Why is tamoxifen described as a partial antagonist?

Answer 21

Results in partially activated transcription as there is only one activation factor recruiting activators involved

Question 22

Mechanism of action for fulvestrant

Answer 22

-Accelerated receptor degradation as a consequence of binding
- inactivation AF1 and 2 leads to reduced nuclear localisation of the inactive oestrogen receptor
Still get nuclear translocation but no activation factors involved = no transcription

Question 23

Synthetic glucocorticoids can be used as?

Answer 23

Anti-inflammatory and immunosuppressive compounds

Question 24

Prednisolone is what type of glucocorticoid ?

Answer 24

Synthetic, anti-inflammatory and immunosuppressant effects

Question 25

Nuclear factor kappa B

Answer 25

Receptor believed to be important in inflammatory signaling

Question 26

Mechanism of action for prednisolone

Answer 26

• With help of a glucose response element, it bind to DNA
  -Once it binds to its receptor, responsible for inhibiting another receptor, nuclear factor kappa B
  -Moves into the nucleus and the effect of the glucocorticoid is to inhibit the function of the receptor

Question 27

Vamorolone is currently in trials for?

Answer 27

Muscular dystrophy where anti-inflammatory component is more important than immunosuppressive effect

Question 28

Pioglitazone is used in treatment for?

Answer 28

Diabetes

Question 29

pioglitazone : is receptor has number of different effect such as?

Answer 29

• Effect in cytoplasm interfering with second messenger systems
• also translocations in the nucleus where it car be heterodimerised with retinoid receptor

Question 30

Mechanism of action for pioglitazone

Answer 30

Binds to peroxisome proliferator activated receptor y (PPARy)
Alters transcription of genes influencing carbohydrate and lipid metabolism
-Activation of PPARy increases transcription of insulin - responsive genes

Question 31

Finerenore in clinical trials for?

Answer 31

Kidney disease and heart failure

Question 32

Aldosterone is important in terms of?

Answer 32

Regulation of water balance and in pathological conditions, the hormone aldosterone via activation of mineralocorticoid receptors (MR), can result in fibrosis (thickening/scarring of tissue)

Question 33

Role of finerenone

Answer 33

To try and reduce the effects of aldosterone by blocking it with finerenone , reducing the incidence of fibrosis

Question 34

Rosiglitazone: despite being approved by regulators, there is issues regarding?

Answer 34

Its cardiovascular safety