Block A Lecture 1 - Agonists and Receptors

Question 1

What do drugs that bind to receptors often resemble?

Answer 1

The natural / endogenous ligand that binds to the receptors structure
(Slide 4)

Question 2

What is an agonist?

Answer 2

A drug or naturally occurring body substance which directly cause a measurable response which may be positive or negative
(Slide 5)

Question 3

What are the 2 main properties an agonist has?

Answer 3

Affinity and Efficacy
(Slide 5)

Question 4

What is affinity?

Answer 4

The property of a drug to bind to a binding site
(Slide 5)

Question 5

What is efficacy?

Answer 5

A measure of the ability of an agonist to activate the receptor and produce a response
(Slide 5)

Question 6

What is Emax?

Answer 6

The maximum response a tissue or organ can produce in response to a drug or other stimulus
(Slide 6)

Question 7

Why does an Emax exist?

Answer 7

As there is a finite number of receptors in a given tissue or organ
(Slide 7)

Question 8

Agonists usually have weak binding (such as van der vaals or hydrogen bonding), what des this result in?

Answer 8

The agonist being able to be washed away
(Slide 7)

Question 9

What is an EC50 value?

Answer 9

The concentration of an agonist required to elicit 50% of the maximal tissue response (Emax)
(Slide 8)

Question 10

What shape does a concentration response curve make when a semi log scale is used?

Answer 10

An S-shaped curve known as a sigmoid
(Slide 9)

Question 11

Why is a concentration response curve useful?

Answer 11

As it allows you to compare the potencies of multiple agonists
(Slide 10)

Question 12

What does the law of mass action state?

Answer 12

That the rate of a chemical process is proportional to the concentrations (M) of the reacting substances
(Slide 12)

Question 13

What is the original equation of the law of mass action?

Answer 13

A + R ⇌ AR complex

A (drug conc) is also known as Xa
R (free receptors) is also known as NTOT (total number of receptors) - NA (occupied receptors)
AR complex is also known as NA

(Slide 12)

Question 14

What equation do you get when you rearrange the law of mass action equation into the Hill-Langmuir equation?

Answer 14

PA = XA/ XA + KD

where PA is the proportion of receptors occupied
XA is the concentration of the agonist
KD is the KD of the agonist
(Slide 13)

Question 15

What happens to the Hill-Langmuir equation when the PA (proportion of the receptors occupied) is equal to 0.5?

Answer 15

0.5 = XA / XA + KD
(times both sides by xA + KD)
0.5 xA + 0.5 KD = XA
simplify:
0.5KD = 0.5 XA
KD = XA
so the KD is equal to the concentration of the agonist

meaning that when 50% of receptors are occupied, KD equals EC50!
(Slide 14)

Question 16

How can agonist concentration response curves in different tissues be used to identify different receptor subtypes?

Answer 16

If the rank of potency is different in receptors A and B are different

e.g Receptor in tissue A Rank:
A>B>C

Receptor in tissue B Rank:
B>A>C

These are 2 different receptor subtypes
(Slide 20)

Question 17

Can the same agonist produce excitation and inhibition?

Answer 17

Yes, by acting on different receptors in different tissues

e.g Acetylcholine producing excitation by acting on M3 receptors in the ileum but inhibition when acting on M2 receptors in the sinoatrial node in the heart
(Slide 22)

Question 18

Can the same tissue contain receptors for more than one agonist?

Answer 18

Yes!
(Slide 22)

Question 19

What is a partial agonist?

Answer 19

Agonists which have particularly low efficacies that cannot produce a maximal response from the tissue no matter how high their concentration is
(Slide 23)

Question 20

How can partial agonists reduce the action of full agonists?

Answer 20

By occupying a large portion of the receptors in a tissue
(Slide 24)

Question 21

Can agonists produce a maximal response without having all the receptors in the tissue occupied?

Answer 21

Yes, if they are particularly potent
(Slide 25)

Question 22

The common belief about receptors was that they were either off (in the absence of an agonist) or on (in the presence of an agonist). What is the belief now?

Answer 22

That some receptors are constitutively active: they are partially active even in the absence of an agonist or other stimuli
(Slide 27)

Question 23

What is the main receptor type that makes up constitutively active receptor?

Answer 23

GPCRs
(Slide 27)

Question 24

What is an inverse agonist?

Answer 24

An agonist which can completely turn off constitutively active receptors
(Slide 27)

Question 25

How can an inverse agonist result in the tissue response being lowered to less than the baseline response?

Answer 25

Usually, on receptors that are always off, the baseline response is 0%. An agonist increases this by partially or fully activating receptors to reach whatever the maximum tissue response the agonist can elicit.

However, constitutively active receptors are always partially active even in the absence of a agonist or other stimuli, meaning the baseline tissue response can be for example 10%. An inverse agonist can turn some, or all, of these receptors off completely, making the tissue response lower than that of the “baseline” (but still not lower than 0%)
(Slide 27)

Question 26

What kind of efficacy do inverse agonists have?

Answer 26

Negative efficacy
(Slide 28)

Question 27

What is the 2 state model?

Answer 27

R (receptor resting state) ⇌ R* (activated state) —-> response
(Slide 30)

Question 28

What does a having no agonist available do to the equilibrium of the two state model?

Answer 28

R (receptor resting state) ⇌ R* (activated state) —-> response
Equation reminder for visualisation purposes

When no agonist is available the equilibrium will lie far to the left (the bottom arrow will be thicker than the top arrow) and most of the receptors will be in the R state with constitutively active receptors being in the R* state

Question 29

What does a full or partial agonist do to the equilibrium of the two model state?

Answer 29

R (receptor resting state) ⇌ R* (activated state) —-> response
Equation reminder for visualisation purposes

A full or partial agonist will move the equilibrium to the right (the top arrow will be thicker)

Note: The greater affinity that the agonist has for the R* state over the R state, the greater the efficacy of the agonist

Question 30

What does an inverse agonist do to the equilibrium of the two state model?

Answer 30

R (receptor resting state) ⇌ R* (activated state) —-> response
Equation reminder for visualisation purposes

The equilibrium will move left (the bottom arrow will be thicker) as the inverse agonist will mean there’s a greater affinity for the R state over the R* state. Most receptors will be in the resting state.

(Slide 31)

Question 31

What were most inverse agonists originally classified as?

Answer 31

Antagonists
(Slide 31)

Question 32

Explain what happens when the “balanced signal” scenario occurs when an agonists binds to a receptor.

Answer 32

When the ligand / agonist binds to the receptor, it activates all downstream signalling pathways that the receptor is capable of activating in a proportional / typical manner. It doesn’t favour 1 signalling pathway other another
(Slide 33)

Question 33

Explain what happens when the “biased agonist” scenario occurs when a agonist binds a receptor.

Answer 33

The agonist selects one signalling over another after binding to a receptor, even though the receptor can activate multiple pathways

Note: The agonist can still activate the pathway it’s not biased to to a lesser extent (though the extent of this varies by agonist)
(Slide 33)

Question 34

Explain what happens when the “biased receptor” scenario occurs when a agonist binds a receptor.

Answer 34

A biased receptor is a receptor that due to their specific conformation or mutations have an intrinsic preference for one signalling pathway over another, when activated by the same ligand and sometimes even when activated by different ligands.

Note: A biased receptor will favour one pathway due to its conformation but may still allow activation of other pathways to a lesser extent. (though the extent of this varies by receptor)
(Slide 33)

Question 35

What are the 2 main types of biased receptors / agonists?

Answer 35

G protein-biased agonists and ß-Arrestin biased agonists
(Slide 33)