ELM 5.1

Question 1

What is a partial agonist?

Answer 1

A drug that cannot fully activate a receptor, even when all the receptors in the system are occupied

Question 2

What is a superagonist?

Answer 2

A drug whose efficacy exceeds that of a (natural) full agonist

Question 3

A partial agonist is a drug with ____ efficacy and ____ affinity

Answer 3

some
some

Question 4

Drug A is a partial agonist at muscarinic acetylcholine receptors with an efficacy of 75%. What is the efficacy of acetylcholine at this receptor?

Answer 4

100%
( the endogenous agonist is classified as a full agonist and has an efficacy of 100% )

Question 5

Do receptors need an agonist to activate?

Answer 5

No, they can spontaneously activate

Question 6

How much has spontaneous activation been observed

Answer 6

many ligand-gated ion channels and ~40% of G protein coupled receptors

Question 7

What is the two state model?

Answer 7

Takes into account spontaneous activation - the receptor is in an equilibrium between an unliganded inactive state and an unliganded active state

Question 8

According to the two state model, what is a full agonist?

Answer 8

a drug that has much higher affinity for the active state of the receptor than for the inactive state

Question 9

What is conformational selection?

Answer 9

When the receptor visits the active state in the presence of a full agonist, the agonist binds and ‘locks’ it in the active state

Question 10

Why does conformational selection happen?

Answer 10

Because the binding energy of the agonist stabilizes the receptor in the active state and prevents it from going back to the inactive state

Question 11

What is the action of antagonists?

Answer 11

They bind equally tightly to the inactive and active states and thus prevents activation by agonists because of competition

Question 12

What ratio does the efficacy of a partial agonist depend on?

Answer 12

Kd(inactive) / Kd(active) (the larger this ratio, the higher the efficacy)

Question 13

What are inverse agonists?

Answer 13

Drugs that bind tighter to the inactive state

Question 14

How do inverse agonists differ from competitive antagonists?

Answer 14

They will reduce spontaneous activation of the receptor

Question 15

What does the Monod Wyman Changeux allosteric model (MWC) state?

Answer 15

the agonist ‘pushes’ the receptor into changing states

Question 16

Compare MWC and KNF theory to Darwin and Lamark

Answer 16

Giraffe
Lamark’s central idea - evolutionary pressure causes changes in an organism which is then passed onto its offspring - like the KNF theory - relies on agonist causing a change
Darwinism - would suggest that there is random change and that evolutionary pressure stablizes certain changes that are favourable - like the MWC model - the agonist stabilizes a change that the receptor is undergoing spontaneously

Question 17

MWC summary

Answer 17

The Monod Wyman Changeux model explains spontaneous activity of receptors and receptor activation by saying that the receptor moves between resting and active states on its own and agonist drugs simply “lock” it into the active state. This is like the two state model.

Question 18

KNF summary

Answer 18

The Koshland Nemethy Filmer model is based on induced fit and suggests that agonists “push” the receptor into the active state. It does not really explain spontaneous activity. This is like the finger and switch model

Question 19

What are non-competitive antagonists?

Answer 19

they bind to a different site on the receptor than the agonist - which is the reason why they do not compete with the agonist

Question 20

What will a non-competitive antagonist do to the EC50 and the maximum response?

Answer 20

No change to the EC50, but will reduce max response

Question 21

How would you properly classify drugs that are ‘non-competitive’?

Answer 21

negative allosteric modulators

Question 22

Functional antagonists

Answer 22

‘phsyiological antagonist’
both drugs are agonists - arises when a tissue has two different types of receptor, which exert opposite effects on the tissue - i.e. pupil of the eye

Question 23

According to the two state model, an antagonist is a drug that has:

Answer 23

equal affinity for the active and inactive states

Question 24

A receptor shows spontaneous activity in the absence of agonist. Which type(s) of ligand would reduce spontaneous activity?

Answer 24

inverse agonist
The receptor can still activate in the presence of an antagonist - the underlying level of spontaneous activity is not affected by antagonists because these drugs do not select between the inactive and active states of the receptor. Inverse agonists bind tighter to the inactive state than the active state, so reduce spontaneous activity.

Question 25

The antagonism of bronchoconstriction by methacholine (muscarinic receptor agonist) by salbutamol (beta adrenoceptor agonist) is an example of __________ antagonism.

Answer 25

functional

Question 26

Which of the following types of drug has the lowest efficacy?

Answer 26

Inverse agonist
Inverse agonists are a continuation of the ligand spectrum past pure antagonist. As a pure antagonist has an efficacy of zero, the efficacy of an inverse agonist must be negative.