Theme 2 Lecture 6

Question 1

Explain what agonism is?

Answer 1

Efficacy- activating the receptor
Affinity- binding to the receptor

Question 2

Do agonists have varied efficacies?

Answer 2

Yes, because it depends on what type of ligands and tissues.
As well as the response relying on signal amplification.

Question 3

What is receptor reserve and the significance in drug response? Cinema

Answer 3

Excess Receptors Present
A drug with a high receptor reserve can achieve a maximal response even when only a portion of the receptors are activated.
This shows efficacy and potency

Question 4

What is the difference between EC50 and kd

Answer 4

EC50 is the concentration of a drug that produces a half maximum response=Efficacy
Kd is the dissociation constant representing the concentration where half the number of the receptors are occupied.=Affinity

Question 5

How do low efficacy agonists affect the response of a receptor system?

Answer 5

They bind to the receptor but have a low response (even when all receptors are occupied)

Question 6

Is there a correlation between EC50 and kD?

Answer 6

EC50=kD
If you need 50% occupancy for 50% maximum response.

Question 7

If there are 10 receptors and 5 are occupied what is the occupancy?

Answer 7

alpha=0.5

Question 8

If there are 10 receptors and the 1 is occupied, what is the occupancy

Answer 8

alpha=0.1

Question 9

Which way would the log curve shift in the case of alpha being 0.1?

Answer 9

To the left of where the binding curve is.

Question 10

What happens if there is a greater signal amplification?

Answer 10

You move further down the pathway.

Question 11

What represents agonist efficacy?

Answer 11

-Efficacy can vary depending on both the ligand and the specific tissue or cell.

Intrinsic efficacy represents the efficacy of the agonist at the individual receptor.

Question 12

Ways to quantify efficacy?

Answer 12

Comparing a maximal response of a partial agonist and a full agonist

Or comparing the ratios of EC50 and kd when max responses are the same

Question 13

Gaddum equation role

Answer 13

Describes the relationship between the concentration of an antagonist and the shift it causes in the dose response curve.

This can then work out dissociation constants of competitive antagonists.

Question 14

Gaddum equation involving A1 AND A2

Answer 14

Add a fixed concentration of an antagonist and you get a shift right
The shift right gives the same size response

A2/A1=1+B/Kb
B is antagonist conc

Question 15

What is Schild analysis and its purpose?

Answer 15

It measures how much antagonist concentration it takes to reduce the effectiveness of the agonist.

It plots the dose ratio-1 (reflecting the shift in agonist dose-response curve due to antagonist presence-shift being to the right) against antagonist concentration to calculate the pA2 value
Thus finding out potency.

Question 16

Non-competitive inhibition

Answer 16

Non-competitive inhibition occurs when an inhibitor binds to a site other than the agonist binding site,

Decreasing maximal response achievable by the agonist

But does not affect the potency or EC50 of the agonist.

Question 17

PA2 value is the what?

Answer 17

The PA2 value is the minus log of the Kb value

Question 18

Slope of 1 means what?

Answer 18

That your antagonist is competitive and is a straight line.

Question 19

Antagonist studies

Answer 19

Usually added 30 mins before
Parallel shift possible with high efficacy agonist and spare receptor reserve (high receptor expression)

Question 20

Signal amplification and spare receptors
look at slide 9 from lecture 3b

Answer 20

Cyclic AMP activates (PKA),

Phosphorylates CREB binding protein.

CREB binding protein interacts with a cyclic AMP response element.

If there is light output then luciferase shows signalling

Question 21

Measuring Cyclic AMP Generation:

Answer 21

-At the level of cyclic AMP generation, you might assess two agonists, one of which is potent, while the effectiveness of the other is debatable due to the small signal produced.

-The measured effect might be so subtle that agreement on its significance could be debated.

Question 22

Gene Expression Level:
Lighter blue curve

Answer 22

-As you move further down the signaling cascade, such as to the level of gene expression, you may observe significant differences.

-The weaker agonist, represented by the darker blue line, now produces a substantial response, approximately 60% of the full agonist response (lighter blue curve).

-Notably, the lighter blue curve also shifts to the left, positioning the EC50 (Effective Concentration 50%) to the left of the KD (Dissociation Constant) value.

Question 23

What is a hemi-equilibrium?

Answer 23

In hemi-equilibrium, the agonist and antagonist have not reached their equilibrium values.