Agonists & Antagonists

Question 1

Define agonist

Answer 1

Favours the active receptor confirmation, binds to a receptor and causes an effect

Question 2

Define antagonist

Answer 2

A drug that prevents the agonist-induced activation of the receptor

Question 3

Law of mass action - AGONISTS

Answer 3

Question 4

Law of mass action - ANTAGONISTS

Answer 4

Question 5

In terms of classifying antagonists, what are the 2 subgroups of those that bind at the agonist site

Answer 5

1. REVERSIBLE - competitive
2. IRREVERSIBLE - competitive

Question 6

Where else can an antagonist bind, other than the agonist site

Answer 6

Binds elsewhere - allosteric site (non-competitive)

Question 7

Define competitive antagonists

What are the 2 types

Answer 7

This type of antagonism is at the binding site of the endogenous ligand

REVERSIBLE - most common and most important type of antagonism

IRREVERSIBLE - covalent bond formation

Question 8

Explain this graph

Answer 8

Antagonist competes with agonist for receptor binding sites

Increasing concentrations of antagonist progressively inhibit the agonist response

High concentrations of agonist can surmount the effect of the antagonist

Question 9

Explain this graph

Answer 9

Antagonist binds with covalent bonds to receptor

Agonist cannot displace antagonist

Question 10

What will the competitive antagonist do

Is it possible to move a non-competitive antagonist

Answer 10

• Compete with the agonist for the binding site => more and more of the agonist needs to be administered (concentration response curve)
• A non-competitive antagonist (purple) cannot be moved by other agonists

Question 11

What happens to an irreversible antagonist at the agonist binding site

Answer 11

Stays bound - cannot be displaced because it dissociates only very slowly (due to nature of bonds)

Question 12

Where would a non-competitive antagonist block

What might this do

Answer 12

At some point other than the receptor binding site

May bind to another site on the receptor (allosteric inhibition)

May block the signal transduction process

Question 13

Why are allosteric antagonists non-competitive

Answer 13

Because they do not bind at the agonist binding site

Question 14

Define chemical antagonism (a type of non-receptor antagonism)

Answer 14

Inactivates agonist by forming a complex with it e.g. protamine is a basic protein that binds to heparin forming an inactive complex

Question 15

Define physiological antagonism (a type of non-receptor antagonism)

Answer 15

Activates/blocks a receptor that mediates a response physiologically opposite to that of the receptor

e.g. histamine acts on parietal cells to stimulate gastric acid secretion, whilst the proton pump inhibitor omeprazole blocks this action

Question 16

What sort of response do partial agonists produce

What is this response due to

What can they act as

Answer 16

• Produce a lower response than full agonists
• Reduced response not due to decreased binding affinity but decreased efficacy
• As partial agonists bind to same site, they can reduce the response produced by a full agonist, thus can acts as competitive antagonist

Question 17

What is buprenorphine a partial agonist of

What does it produce

How does it compare to morphine

Answer 17

• u opioid receptors
• Produces a submaximal relief of analgesia when compared to morphine
• As a result, ought to have less addiction liability than morphine

Question 18

Explain the 2 theories for the molecular basis of partial agonism

Answer 18

1. The partial agonist is a good fit for the receptor binding site, but less able to promote the receptor conformational change leading to transduction
2. The receptor may be in an active and inactive state, and that partial agonists form complexes with both states, whereas full agonists preferentially bind the active form

Question 19

What does the 2-state receptor model account for

What are the 2 states & what are they favoured by

Answer 19

• Accounts for the fact that
  
  • Agonists bind receptors and activate them
  • Antagonists bind but do not activate
• Can be in 1 of 2 states:
  
  • Resting (R)
  • Activated (R*)
• Binding an agonist favours the active (R*) state
• Binding an antagonist favours the resting (R) state

Question 20

What state would an unbound receptor be in

Answer 20

Normally in R state

Question 21

In the unbound state, what do some receptors have

Name 3 examples

What can cause this phenomenon

Answer 21

• A degree of acitivity - in the R* state
• => constitutively active
• e.g. cannabinoid receptors, benzodiazepine receptors, serotonin receptors
• Disease causing mutations can cause a receptor to become constitutively active

Question 22

What does an inverse agonist do

Answer 22

Binds to receptors, reduces the fraction of them in an active conformation and has biological effects OPPOSITE to those produced by an agonist

Question 23

What does an inverse agonist do when it binds to a constitutively active receptor

Answer 23

REDUCES its activation => NEGATIVE EFFICACY

Question 24

Graphic depiction of inverse agonists

Answer 24

Question 25

Give 2 examples of inverse agonists

Answer 25

• A beta blocker does not simply “block” the receptor, but further inactivates receptor activity beyond its baseline value, and thus possesses inverse agonist activity e.g. propranolol
• H2 receptor antagonists, e.g. cimetidine, act as inverse agonists and diminish basal cAMP levels associated with gastric acid secretion

Question 26

Explain biased agonists

Answer 26

• The classical idea of an agonist is that it activates the whole repertorie of signals following activation
• “Selectivity” thus based on a specific receptor type/subtype
• Partial agonists and inverse agonists still fed into the 2-state model
• Now, a revision of the theory suggests that receptor coupling results in myriad configurations (states), and that ac certain configuration may elicit a specific subset of signalling response

Question 27

How does the Ang II type I receptor signal

What is TRV027

What could it be used to treat

Answer 27

• Through G protein and beta arrestin-dependent pathways
• TRV027 is a selective beta-arrestin-biased ligand without activating G protein
• May prove useful for treating acute heart failure

Question 28

What are the on-target effects of activating G-protein

Answer 28

Produce analgesia

Question 29

What sort of effects does activating the beta-arrestin pathway cause

Answer 29

Adverse effects (depression, nausea)

Question 30

What is TRV130

Answer 30

A strong agonist of the u opioid receptor but selective for activating the G protein pathway and not the beta-arrestin pathway