Agonists

Question 1

What is a receptor?

Answer 1

A protein target with which a naturally occurring chemical mediator binds specifically to initiate a cellular response.

Question 2

What route must a chemical mediator take if it is large and/ or hydrophilic?

Answer 2

They rely on cell surface receptors.

Question 3

What route can a chemical mediator take if it is small and / or hydrophobic?

Answer 3

These can pass through the membrane and directly activate intracellular receptor proteins.

Question 4

How would you describe the shape change of a receptor upon binding with a chemical mediator?

Answer 4

The shape change stabilises the active form of the receptor and enhances the interaction with signal transduction mechanism.

Question 5

What are the five factors that affect the size of a response to a receptor agonist?

Answer 5

1) Concentration of drug (agonist)
2) Affinity of drug to receptor
3) Intrinsic efficacy (ability to activate)
4) Nature of receptor-response coupling
5) Total number of receptors present

Question 6

When is a maximum response observed?

Answer 6

When all receptors present are occupied by the agonist.

Question 7

How do you describe the binding of an agonist with a receptor?

Answer 7

Agonist receptor complex

Question 8

The fraction of the total number of receptors available which are occupied depends on?

Answer 8

Agonist concentration
Strength of bonds formed

Question 9

What is the rate of a reversible reaction proportional to?

Answer 9

The product of the concentration of the reactant

Question 10

What is the equation for the forward rate of a reaction (K+1)?

Answer 10

[free receptor][agonist]

Question 11

What is the equation for the backwards rate of a reaction (K-1)?

Answer 11

[agonist - receptor complex]

Question 12

How do you describe the reaction rate at equilibrium?

Answer 12

Forward = backwards

Question 13

K+1 [Ntot - Na] [Xa] = K-1 [Na]
Describe the equation

Answer 13

Ntot = total number of receptors present
Na = number of receptors occupied by agonist
Ntot-Na = number of unoccupied receptors
Xa = concentration of agonist within the vicinity of receptors

Question 14

What is the fractional occupancy equation?

Answer 14

Na/Ntot = [Xa] / ([Xa] + Ka)

Question 15

What is Ka?

Answer 15

Equilibrium constant for agonist A

Question 16

How does the occupancy change as Ka changes?

Answer 16

The smaller Ka the higher the occupancy
The bigger Ka the lower the occupancy

Question 17

What is important to remember about Ka at 50% occupancy?

Answer 17

Ka is numerically equal to the concentration of agonist when half of the total receptors present are occupied

Question 18

Why is there lower binding with a higher Ka?

Answer 18

Higher Ka value means lower affinity (strength of binding) of agonist for receptor.

Question 19

How is the actual response of a drug simulated?

Answer 19

Preforming a Bioassay

Question 20

Outline the steps of a bioassay

Answer 20

Muscle strip (usually intestine) set up in an organ bath
Use a suitable physiological medium
Oxygenate the bath
Maintain physiologic temperature
When agonist is added record the rate of contraction seen using a computer programme

Question 21

Define what an EC50 is

Answer 21

The effective concentration needed to produce 50% of the maximum response

Question 22

What is the difference between Ka and EC50?

Answer 22

Ka is a theoretical measure of affinity of agonist receptor complexes as an isolated entity.
EC50 is practical and indirect, measures drug potency downstream of receptor. Relates agonist concentration to biological effect produced by

Question 23

Describe receptor activation
(Intrinsic efficacy)

Answer 23

The ability of an agonist on binding to a receptor to activate a change in shape of the receptor
Shape change is needed to couple the receptor to the signal transduction mechanism

Question 24

What do full agonists do?

Answer 24

Produce the maximum response of which the tissue is capable of during the activation of all that population of receptors

Question 25

What does a partial agonist do?

Answer 25

Produce a smaller (less than max) response even when at very high concentrations

Question 26

What are the intrinsic efficacy values of full vs partial agonists

Answer 26

Full = +1 (dobutamine at beta1 adrenoceptors)
Partial = 0 - 1 (pindolol at beta1 adrenoceptors)

Question 27

What are the 3 stages of cell signalling?

Answer 27

Reception (binding, activation)
Transduction
Response

Question 28

What are the 4 types of coupling that affect the amplification of the signal and response seen?

Answer 28

Chemical gating of ion channels
Activation of G protein linked to ion channels or enzymes
Direct activation of enzymes
Regulation of gene transcription

Question 29

How do receptor numbers affect the size of response?

Answer 29

The more receptors for a particular agonist the higher that response will be.
A cell may express multiple receptor types but even if they’re all full it is the most common type that will have a bigger impact

Question 30

What is desensitisation?

Answer 30

The reduction in size of a response during chronic exposure to an agonist drug

Question 31

What happens during desensitisation?

Answer 31

Increased removal/ metabolism of the agonist
Altered characterisation of agonist receptor complex
Down regulation of signal transduction mechanisms downstream from receptor
Decreased number of receptors (decreased synthesis and increased internalisation)
Reflex activation of opposing pathways

Question 32

What impact do spare receptors have?

Answer 32

The amplification of the initial signal by the signal transduction cascade is so great that actual max response occurs at <100% occupancy

Question 33

What do inverse agonists do?

Answer 33

Cause a shape change that makes it harder to activate the receptor

Question 34

What is the intrinsic efficacy value of an inverse agonist?

Answer 34

Between -1 and 0
They inhibit basal activity as well as stabilise the inactive form

Question 35

What is the difference between antagonists and inverse agonists?

Answer 35

Inverse agonist stop/ reduce basal activity
Antagonists only prevent a response by stopping another agonist from binding