Full & Partial Agonists (Lecture 10)

Question 1

What is the difference between full & partial agonists?

Answer 1

Full agonists - can produce a MAXIMAL tissue response

Partial agonists - cannot produce a maximal tissue response, regardless of how high their concentration is

Question 2

What is meant by agonist efficacy ?

Answer 2

The ability of the agonist to stabilise the active state of the receptor

I.e. AR <—> AR*

Question 3

What is the Del Castillo model of receptor activation, and what does it take into account?

Answer 3

Takes into account the activation of the receptor:

Step 1 (k+1): Binding of the agonist, equilibrium constant
A + R <—> AR

Step 2 (E): Conformational change to an active state
AR <—> AR*

Question 4

What are the full and partial agonists of B-adrenoreceptors?

Answer 4

Full - adrenaline, isoprenaline

Partial - prenalterol

Question 5

What are the full & partial agonists of Histamine H2 receptors?

Answer 5

Full - histamine

Partial - impromidine

Question 6

What are the full & partial agonists of beta-adrenoreceptors?

Answer 6

Partial - prenalterol

Full - adrenaline, isoprenaline

Question 7

What are spare receptors and why are they important?

Answer 7

Tissues have ‘spare receptors’ - more receptors than needed to produce a maximum response (i.e. if sufficient ion channels are open to fully depolarise a cell, opening more won’t give a bigger response)

The number of spare receptors is important with a partial agonist as this determines the maximum response - a partial agonist for one tissue could act as a full agonist for another if there is a large enough number of receptors

Question 8

What is desensitisation?

Answer 8

Tissue response decreases despite continued presence of agonist

Question 9

How can desensitisation happen?

Answer 9

Agonist-bound ligand gated ion channels in the activated state (AR*) can isomerise to an inactive, desensitised state

Phosphorylation of receptors on GPCRs by one or more protein kinases (activated by agonist binding) can be followed by a loss of some receptors from the cell surface

Question 10

What does comparing the effect of:
1. Increasing concentrations of partial agonists on tissue response
2. A fixed concentration of full agonist on tissue response

Show?

Answer 10

That the partial agonist is able to combine with all the receptors, provided it has a high enough concentration, however the tissue response is less than when using a full agonist

Partial agonist reaches submaximal response, then plateaus as concentration increases - shows that it won’t reach the maximal response produced by the full agonist

Question 11

What does adding low concentrations of a full agonist to a partial agonist show?

Answer 11

Increases the response but concentration-response curves will cross as [full agonist] is increased.

This is because the presence of the partial agonist reduces the number of available receptors (to the full agonist) - therefore the partial agonist reduces the response to the full agonist

Question 12

What 2 ways can we rule out the explanation that partial agonists have a smaller effect because they are not able to combine with all of the receptors?

Answer 12

1. Comparing the effect of increasing the concentrations of a partial agonist on tissue response, with the tissue response with a fixed concentration of full agonist
2. Adding low concentrations of a full agonist to a partial agonist

Question 13

Why are some agonists (i.e. full agonists) better able to stabilise the active receptor conformation than others?

Answer 13

Due to bonds / interactions they make with the receptor

Question 14

What is the difference between a partial & full agonist?

Answer 14

Their ability to ACTIVATE (rather than bind to) the receptor

In a partial agonist, AR —> AR* rate may be slow, but AR* —> AR will be faster as there are fewer bonds holding it in the active state

Question 15

What are Slow-Channel Congenital Myasthenic Syndromes (SCCMS) and what are they characterised by?

Answer 15

Disorders of neuromuscular transmission

Characterised by muscle weakness & fatiguability (caused by degeneration of the junctional folds)

Mutations cause prolonged endplate currents - shown by changes in both the binding & efficacy of ACh

Question 16

What is the difference between what would be shown by a healthy ‘wild type’ channel and an SCCMS mutant channel? (On the line graph thing)

Answer 16

Healthy ‘wild type’ channel - mostly closed but opens in bursts when ACh is bound

SCCMS mutant - channel is open for a longer time - difference in ACh efficacy & binding

Question 17

What are the characteristics of a negative / inverse agonist for a constitutively active receptor?

Answer 17

A + R (inactive) —-> AR (inactive)

• doesn’t cause a conformational change to the receptor
• only combines with inactive receptors (R)
• promoting the formation of (inactive) AR
• thus reducing the proportion of active receptors (R*)

Question 18

What are the characteristics of a conventional agonist for a constitutively active receptor?

Answer 18

Constitutively active receptor: R (inactive) <——> R* (active)

• conventional agonist only combines with active receptor (R*)
• promoting the formation of (active) AR* (A + R* <—-> AR*)

Question 19

What are the characteristics of a reversible competitive agonist for a constitutively active receptor?

Answer 19

Constitutively active receptor: R (active) <—> R* (active)

• reversible comp agonist doesn’t cause a conformational change to the receptor
• has equal affinity for both R & R*
  A + R —> AR
  A. R* —> AR*
• therefore doesn’t affect the proportion of receptors in the active R* state

Question 20

What are constitutively active receptor?

Answer 20

Receptors which activate in the absence of agonist - random collisions can provide enough thermal energy for the receptor to assume the active conformation

R(inactive) <—> R* (active)

Question 21

Describe receptor activation (agonist efficacy)

Answer 21

• receptors (e.g. GPCRs / ligand-gated ion channels) are activated by agonists binding - which causes a conformational change in the receptor
• on binding, receptors (e.g. H-H bonds / charge-charge interactions) which stabilise the active conformation of the receptor
• this conformational change is reversible, at some point, the receptor-agonist complex will have enough thermal energy to break the bonds holding them in the active conformation
• some agonists (e.g. full agonists) are better able to stabilise the active receptor conformation (AR*) than others (e.g. partial agonists) due to the bonds / interactions they make with the receptor

Question 22

What is the difference between the dose-response curves for full and partial agonists?

Answer 22

Full agonist - curve saturates at high concentrations - indicating that it has reached its maximum response

Partial agonist - curve reaches a plateau at a lower level than the full agonist, despite increasing concentrations - indicating that it cannot produce the same maximal effect

Question 23

Where might partial agonists be advantageous over full agonists in treatment?

Answer 23

In situations such as…
- where too much receptor activation may be harmful
- where the desired biological response is less than the maximum possible

Question 24

What is the different between the efficacy of partial and full agonists ?

Answer 24

Partial agonists have a LOWER EFFICACY than full agonists