Lecture 3

Question 1

What are agonists?

Answer 1

Receptor activators

Question 2

What are antagonists?

Answer 2

Receptor blockers

Question 3

What is a receptor?

Answer 3

A protein which binds to neurotransmitters, hormones etc and produces a cellular response

Question 4

Name the two types of receptors

Answer 4

• ionotropic - metabotropic

Question 5

What is another name for iontropic receptors?

Answer 5

Ligand gated ion channels

Question 6

What is another name for metabotropic receptors?

Answer 6

G-protein coupled receptors

Question 7

Mechanisms of agonists

Answer 7

Binding to receptor -> AR complex -> conformational change of receptor= response

Question 8

How do we measure responses to a drug?

Answer 8

• muscle contraction- second messenger production e.g. cAMP, IP3 - inhibition of transmitter release - change in HR, BP etc

Question 9

What shape is the agonist log concentration-response curve?

Answer 9

Sigmoidal

Question 10

What is EC50?

Answer 10

Effective concentration giving 50% of maximal response

Question 11

Why is there a maximum response?

Answer 11

• finite number of receptors which are all occupied- response is proportional to the AR complex - property of tissue/cell e.g. maximal muscle contraction

Question 12

What is affinity?

Answer 12

How well a drug binds to a receptor

Question 13

What is efficacy?

Answer 13

A measure of the response once the drug is bound to a receptor

Question 14

What is potency?

Answer 14

A combination of affinity and efficacy

Question 15

Do drugs with the same EC50 always have the same efficacy?

Answer 15

No- drugs can have the same affinity but one drug can have higher efficacy than the other

Question 16

What is Kd?

Answer 16

Concentration of drug required to occupy 50% of the receptors

Question 17

What does a low Kd mean?

Answer 17

high binding affinity

Question 18

Why can you not measure a response of ligand affinity?

Answer 18

Because you can have high affinity but low efficacy and vice versa- you have to look at binding

Question 19

Mechanism of a ligand binding assay?

Answer 19

Displacement of radio-labelled ligand (3H, 14C, 125I) by a cool ligand

Question 20

What is an issue of using a ligand binding assay?

Answer 20

Must account for non-specific binding e.g. to plasma proteins

Question 21

How do we deal with non-specific binding in ligand binding assays?

Answer 21

Increase amount of cold ligand to displace radio-labelled ligand, ensuring that only NSB only occurs with radio-labelled ligand

Question 22

Why do we see receptor desensitisation?

Answer 22

• loss of receptors (internalisation) - exhaustion of mediators e.g. cAMP - physiological adaption (homeostatic response)

Question 23

What is tachyphylaxis?

Answer 23

rapidly diminishing response to successive doses of a drug, rendering it less effective

Question 24

What is the difference between desensitisation and tachyphylaxis?

Answer 24

Tachyphylaxis is a possible mechanism underlying desensitsation

Question 25

Examples of agonists used clinically

Answer 25

Adrenaline, salbutamol. dopamine, morphine

Question 26

What is a partial agonist?

Answer 26

- cannot produce a full response (low efficacy) - prevents full agonists - reduces overactivity without reducing basal activity

Question 27

Why do we use buprenorphine (temgesic) as a partial agonist?

Answer 27

- less abuse liability - less dysphoria

Question 28

What are inverse agonists?

Answer 28

Agonists that produce the opposite response of a full agonist

Question 29

Why do we use inverse agonists?

Answer 29

To reduce the constitutive activity (activity without a ligand) of GPCRs

Question 30

What would an inverse agonist do at the GABA-A receptor?

Answer 30

Decreases the activity of GABA

Question 31

What is a PAM?

Answer 31

Postive allosteric modulator

Question 32

What do PAMs do?

Answer 32

Increases coupling to a G protein which makes the agonist more effective

Question 33

What is a NAM?

Answer 33

Negative allosteric modulator

Question 34

What do NAMs do?

Answer 34

Reduce effectiveness of the G protein

Question 35

What is an AGO-PAM?

Answer 35

An agonist with positive allosteric modulatory activity

Question 36

Why would you use a PAM/NAM?

Answer 36

If you want to increase/reduce activity but don't want to change the regular temporal pattern, modulate the activity of agonists

Question 37

What is a competitive antagonist?

Answer 37

- reduces EC50 of an agonist - parallel shift in concentration-response curve - can still achieve a maximum response with increased agonists

Question 38

What is pA2?

Answer 38

A measurement of antagonist potency

Question 39

Define pA2

Answer 39

Negative log of the molar concentration of antagonist that reduces the effect of a known agonist concentration by half

Question 40

What does a larger pA2 value mean?

Answer 40

The better an antagonist is

Question 41

Why do we have to consider receptor selectivity for antagonists with high pA2 values?

Answer 41

- higher pA2= less selective an antagonist is - risk of antagonising receptors which were not intended

Question 42

Examples of competitive receptor antagonists

Answer 42

- naloxone - chlorpromazine - beta blockers - atropine - tubocurarine

Question 43

What is a non-competitive antagonist?

Answer 43

- cannot be outcompeted - bind to allosteric site/covalently bound to binding site - no parallel shift or maximum response

Question 44

What is the importance of spare receptors?

Answer 44

- allows max response without occupying all receptor (increased sensitivity) - maybe prevent exaggerated responses

Question 45

How do spare receptors affect Kd and EC50?

Answer 45

Kd ≠ EC50

Question 46

Examples of non-competitive antagonists

Answer 46

- ketamine (NMDA) - perampanel (AMPA) - 𝛼-bugarotoxin (nicotinic)

Question 47

What is drug use-dependence (activity/frequency dependence)?

Answer 47

The more receptors a drug preferentially blocks, the more effective it is (basal activity is preserved)

Question 48

Examples of drugs with use dependence

Answer 48

- epilepsy voltage gated Na+ channels (only block during overactive moments) - cardiac arrythmias Na+ channels (block over active rhythms)