Unit 4 - Receptor pharmacology

Question 1

What is an antagonist?

Answer 1

Bind to the receptor in such a way that they produce a different induced fit and do NOT activate receptor
- block natural messenger so cannot bind and activate

Question 2

What is an agonist?

Answer 2

Bind to the receptor binding site in a similar way to the natural messenger and activates receptor

Question 3

What is selectivity?

Answer 3

Relative affinity
- ligand has higher affinity for one receptor over another
Ligand will preferentially bind to one receptor more avidly than another
- at a lower concentration

Question 4

What effect does better selectivity have?

Answer 4

Fewer side effects

Question 5

Give examples of selective and non selective drugs

Answer 5

Atenolol - selective B1-adrenoceptor antagonist

Propranolol - non-selective B1-adrenoceptor antagonist

Question 6

What effect does a drug with a low affinity have?

Answer 6

Need to have a higher concentration of drug to produce a response

Question 7

How can selectivity be observed?

Answer 7

Response profiles
- not used any more
Concentration response curves
Radioligand binding
- direct method of measuring affinity of ant/agonist for a receptor

Question 8

How are most receptors distributed?

Answer 8

Most receptors are not ubiquitously distributed

- distributed in discrete tissues/organs in the body

Question 9

How is assaying selectivity carried out?

Answer 9

Different tissues can express different populations of receptor types

Question 10

How do non-selective drugs affect tissues?

Answer 10

Non-selective drugs affect all tissues

Question 11

How do selective drugs affect tissues?

Answer 11

Selective drugs affect some tissues but not all tissues

- response in SOME tissues

Question 12

What type of adrenoceptor subtypes are found in the heart?

Answer 12

Beta 1

Beta 2

Question 13

What effect does adrenaline have on beta 1 and beta 2 adrenoceptors in the heart?

Answer 13

Adrenaline is non-selective

• will affect both types of receptor
• heart rate increases
• coronary flow increases
• vasodilation

Question 14

What effect does dobutamine have on beta 1 and beta 2 adrenoceptors in the heart?

Answer 14

Dobutamine is selective for Beta 1 adrenoceptor

• heart rate increases
• no effect on coronary flow

Question 15

What effect does salbutamol have on beta 1 and beta 2 adrenoceptors in the heart?

Answer 15

Salbutamol is selective for Beta 2 adrenoceptor

• no effect on heart rate
• coronary flow increases
• vasodilation

Question 16

How can selectivity be revealed in tissue containing different receptor subtypes?

Answer 16

Concentration response curves

• non-selective agonist
• affinity for receptor is pretty much the same
• sees entire receptor population as the same so targets equally
• selective agonist
• multiple curves
• 2 stacked on top of each other
• 2 EC50 values
• 2 affinity types

Question 17

What is the function of radioligand binding?

Answer 17

Determines binding affinity of ligand for binding site
Affinity is a constant for a ligand-binding site
- receptor
- EXCEPTION
- different affinity states due to G-protein binding
Efficacy is NOT a factor
- no distinction between agonists and antagonists

Question 18

What are the two types of radioligand binding?

Answer 18

Saturation

Competition binding

Question 19

What is saturation binding?

Answer 19

Add radioligand to sample of tissue
- drug labelled with radioactivity
Wash unbound drug away
Measure the amount of radioactivity from sample

Question 20

What is specific binding?

Answer 20

Only interested in binding to the receptor

- specific

Question 21

Describe specific binding

Answer 21

Saturable

• finite number of receptors to bind to
• upper limit
• the number of receptors present
• plataeu when all the receptors are full

Question 22

Describe non-specific binding

Answer 22

Non-saturable

- will always increase with increasing addition of ligand

Question 23

What can be worked out from saturation binding?

Answer 23

Dissociation constant, KD
- affinity constant, KA
- 1/KD
Maximum specific binding
- total number of receptors present

Question 24

What is competition binding?(radioligand)

Answer 24

Add one concentration of radioligand
Displace radioligand from receptors with unlabelled ligand
- increasing concentration of unlabelled ligand
Radioligand and ‘cold’ ligand can be the same
- simplifies things
- but often use known radioligand with known affinity for receptor
Affinity is calculated based on the relative affinities and concentration of radioligand
- known concentration and affinity of radioligand

Question 25

Why does the radioactivity in competition binding never go to zero?

Answer 25

Non specific not bound to receptor so can’t be displaced

Question 26

How did scientists know there were 2 histamine receptors?

Answer 26

In 1948, histamine antagonists already clinically used
- to treat ulcers
- H1 receptor selective
Histamine caused gastric acid secretion
- insensitive to available antihistamines
- suggested presence of a second type of histamine receptor
Clinical utility for treatment of peptic ulcers