Agonist to Antagonist Spectrum

Question 1

What do full agonists do?

Answer 1

activate the receptor to the maximum degree possible – they have maximum efficacy

Question 2

What do antagonists do?

Answer 2

do not activate the receptor at all and have zero efficacy

Question 3

What is the efficacy of a partial agonist and what does that mean?

Answer 3

• Partial agonists: efficacy is in between that of a full agonist and an antagonist
• A partial agonist is a drug that cannot fully activate a receptor, even when all the receptors in the system are occupied
• No matter how much we increase the concentration of the partial agonist, we can’t get as big a response as with high concentrations of the full agonist. This isn’t related to their potency: the two drugs have the same EC50 value

Question 4

Is the efficacy of a partial agonist related to potency? Why/why not?

Answer 4

It is not related to potency, a partial agonist and a full agonist have the same EC50 value

Question 5

How can we quantify agonists to antagonists?

Answer 5

in terms of % efficacy, with antagonists at 0% and full agonists at 100%

Question 6

Why are we interested in partial agonists?

Answer 6

• For some therapeutic targets, partial agonists can be valuable as drugs
• Due to their lower efficacy, they will block the actions of the natural agonist but will still give some receptor activation
• This means they impose a ‘ceiling’ on receptor activity

Question 7

How does the expanded agonist to antagonist spectrum work?

Answer 7

• In this expanded classification system, the natural agonist is classified as a full agonist and all efficacy measurements are made relative to this compound
• A super-agonist is a drug whose efficacy exceeds that of a full agonist

Question 8

What is the spectrum for the 5HT3 receptor?

Answer 8

The 5HT3 receptor is a ligand gated ion channel whose natural agonist is serotonin. Using an electrophysiological assay, Alix et al (2016) characterised a series of compounds whose efficacy varied from zero to 186% relative to serotonin (100%)

Question 9

Do receptors need to bind a ligand to activate?

Answer 9

Occasionally they can spontaneously activate

Question 10

What is the two state model?

Answer 10

receptors can either be liganded and active or inactive or unliganded and active or inactive

Question 11

How do agonists work according to the two state model?

Answer 11

• According to the two state model, a full agonist is a drug that has much higher affinity for the active state of the receptor than for the inactive state. The consequence of this is that when the receptor visits the active state in the presence of a full agonist, the agonist binds and ‘locks’ it in the active state. This is called conformational selection
• Conformational selection happens because the binding energy of the agonist stabilises the receptor in the active state and prevents it from going back to the inactive state.

Question 12

How do antagonists work according to the two state model?

Answer 12

• Antagonists bind equally tightly to the inactive and active states. This prevents activation by agonists because of competition
• Because they bind to both states with equal affinity, an antagonist does not disturb the initial equilibrium between inactive and active states.
• The implication of this is that when an antagonist is bound, the receptor will spontaneously activate at the same rate as when no ligands are bound

Question 13

What do partial agonists do according to the two state model?

Answer 13

• A partial agonist is a molecule that binds tighter to the active state than the inactive, but does not select between the two states as much as a full agonist does. The efficacy of a partial agonist depends on the ratio: Kd(inactive)/ Kd(active)
• The larger the ratio, the higher the efficacy

Question 14

According to the two-state model what do inverse agonists do?

Answer 14

• Inverse agonists bind tighter to the inactive state.
• They differ from competitive antagonists in that they will reduce spontaneous activation of the receptor. However, for most receptors, spontaneous activation is rare and difficult to detect, so it can be hard to distinguish inverse agonists from competitive antagonists

Question 15

What is the conformational selection that underpins the two-state model related to?

Answer 15

a more general model of how proteins operate, called the Monod Wyman and Changeux model (MWC)

Question 16

What does the induced fit model state?

Answer 16

The induced fit model (Koshland Nemethy Filmer) states that the agonist ‘pushes’ the receptor into changing states. In its pure form, the KNF model doesn’t account for spontaneous opening

Question 17

What would a model that has features of both the MWC-based model and the KNF model look like?

Answer 17

In this scheme the receptor can activate spontaneously and the active state is stabilised by the binding energy of the agonist. However, it’s also possible for induced fit to drive the receptor into the active state. This could either happen simultaneously with binding or sequentially after the agonist has initially bound to the inactive state.

Question 18

What do non-competitive antagonists do?

Answer 18

• Non-competitive antagonists bind to a different site on the receptor to the agonist
• Rather than increasing the EC50 and moving the concentration response curve to the right, with no change in maximum effect, a pure non-competitive antagonist will not change the EC50 but will reduce the maximum response.
• This suppression of the maximum response cannot be overcome by increasing the agonist concentration

Question 19

What are functional/physiological antagonists?

Answer 19

• In this type of antagonism both drugs are agonists
• It arises when a tissue has two different types of receptor, which exert opposite effects on the tissue. For example the pupil of the eye: