Theme 2 Lecture 6 Flashcards
Explain what agonism is?
Efficacy- activating the receptor
Affinity- binding to the receptor
Do agonists have varied efficacies?
Yes, because it depends on what type of ligands and tissues.
As well as the response relying on signal amplification.
What is receptor reserve and the significance in drug response? Cinema
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
What is the difference between EC50 and kd
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
How do low efficacy agonists affect the response of a receptor system?
They bind to the receptor but have a low response (even when all receptors are occupied)
Is there a correlation between EC50 and kD?
EC50=kD
If you need 50% occupancy for 50% maximum response.
If there are 10 receptors and 5 are occupied what is the occupancy?
alpha=0.5
If there are 10 receptors and the 1 is occupied, what is the occupancy
alpha=0.1
Which way would the log curve shift in the case of alpha being 0.1?
To the left of where the binding curve is.
What happens if there is a greater signal amplification?
You move further down the pathway.
What represents agonist efficacy?
-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.
Ways to quantify efficacy?
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
Gaddum equation role
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.
Gaddum equation involving A1 AND A2
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
What is Schild analysis and its purpose?
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.
Non-competitive inhibition
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.
PA2 value is the what?
The PA2 value is the minus log of the Kb value
Slope of 1 means what?
That your antagonist is competitive and is a straight line.
Antagonist studies
Usually added 30 mins before
Parallel shift possible with high efficacy agonist and spare receptor reserve (high receptor expression)
Signal amplification and spare receptors
look at slide 9 from lecture 3b
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
Measuring Cyclic AMP Generation:
-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.
Gene Expression Level:
Lighter blue curve
-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.
What is a hemi-equilibrium?
In hemi-equilibrium, the agonist and antagonist have not reached their equilibrium values.
