Receptor theory III Flashcards
How is the response of a drug measured?
In a bioassay
- Apply different concentrations of drugs and measure the outcome
What does a response curve look like?
- Similar to an affinity curve
- Sigmoidal shape which reaches a maximum
What is measured in response curves and what is this?
Ec50
The concentration of the drug which gives 50% of the maximal response
What is the difference between Ec50 and Kd for a FULL AGONIST?
- Ec50 is a measure of the concentration of the drug which gives 50% the maximal response
- In a concentration- response curve
- Kd is the concentration of drug at which 50% of the receptors are occupied
- In a concentration- binding curve (Langmuir plot)
What is the relationship between Ec50 and Kd of a FULL AGONIST?
- Ec50 is shifted to the left of Kd for that particular concentration (NOT EQUAL)
- NOT 50% occupancy with 50% response!!!
- Less occupancy needed for more response
- Shifted to the left due to amplification through secondary messengers
- Smaller concentration to produce 50% response
What is a receptor reserve and why is this important?
Spare receptors in a tissue, which are more than is needed to produce a maximum response
Can afford to lose receptors in tissues without impacting the function of the tissues
If increase partial agonist concentration - can bind to the receptors in the receptor reserve and produce a closer o maximum response
If increase full agonist concentration - no change in the maximum response
How does the response curve not match the binding curve and why is this?
The response curve is shifted to the left of the binding curve (Ec50 is lower than KD)
Because there is AMPLIFICATION in the system through secondary messengers
What is the maximum response determined by?
Efficacy
What does the dose-response curve location on the graph depend upon? (left to right)
The POTENCY of the drug, which is dependant on:
- Affinity
- Efficacy
- Receptor reserve
What does the hill equation describe?
The relationship between the SIZE of the response and the CONCENTRATION of the agonist added
What does the hill coefficient tell you and what is this related to?
How steep the slope is
Related to:
How many molecules of agonist is needed to bind to a receptor to generate a response
How many molecules of agonist is needed to bind to a receptor to generate a response and what is the exception?
Normally 1
But can be 2, for example, for ligand gates ion channels
What can be used to predict the response for any concentration of drug?
The hill equation
Why can’t a low Ec50 be used to conclude that that drug has the highest affinity for a certain receptor?
- Ec50 determines the potency
- The lower the Ec50, the higher the potency
But potency is determined by:
- Affinity
- Efficacy
- Spare receptors
What does increasing the spare receptors in a tissue do to the response curve and why?
- Shifts it to the left
- Higher the probability of the receptor to encounter a ligand
- Increase potency
What can drawing up many dose-response curves show when testing them in different tissues (with the same ligand/receptor pair)
WHY this and not the other factors that are determined by potency?
Which tissue has the most spare receptors
Cant be affinity as it is the ‘same receptor-ligand pair’ - Kd (and affinity) is CONSTANT in this case
What are partial agonists?
Agonists which cannot produce the maximum response
What do agonists with different efficacies produce?
Different maximal responses
Does a partial agonist have a higher or lower efficacy than a full agonist?
A lower efficacy - produces less than maximum response
What is the relationship between efficacy and affinity?
No relationship
An agonist with a high affinity can have a low efficacy
What is the relationship between EC50 and Kd for a partial agonist and why?
They are equal
Why:
- For a partial agonist to make a max response, need 100% occupancy
- So, conc of drug producing 50% of response is the same as 50% occupancy
What is the ‘potency’ of a drug?
The concentration of a drug needed to produce a specific intensity of response
Describe the dose-response curve
Sigmoidal graph
Concentration of AGONIST vs % of maximum response
Which graph is the dose-response curve similar to?
Affinity (langmuir)
What can the dose-response curve be used to work out?
EC50 (concentration of agonist where there is 50% of maximum response)
Why are antagonists not referred to as ‘full’ or ‘partial’
Because is refers to the level of response in the tissue (is it maximal or not)
Antagonists do not cause a response in the tissue
Does potency refer to antagonists?
Why?
No - they do not produce a response in the tissue
