Agonist and dose-response curves

Question 1

What is an agonist?

Answer 1

A ligand that combines with receptors to elicit a cellular response.

Question 2

What dose of aspirin is required to relieve a headache?

Answer 2

300-600mg

Question 3

What is a graded dose-response relationship?

Answer 3

Response of a particular system (isolated tissue), measured against agonist concentration

Question 4

What is a quantal dose-response relationship?

Answer 4

Drug doses (agonist or antagonist), required to produce a specific response determined in each member of the population.

Question 5

What does affinity describe?

Answer 5

The strength with which an agonist/drug binds with a receptor

Question 6

What does Emax allow?

Answer 6

Efficiency to be determined

Question 7

What does EC50 allow?

Answer 7

Potency to be determined

Question 8

What is Bmax?

Answer 8

Maximum number of binding sites

Question 9

What is K1?

Answer 9

The rate of association of the agonist with the receptor

Question 10

What is K-1?

Answer 10

The rate of AR complex dissociation

Question 11

What does affinity equal?

Answer 11

K1 / K-1

Question 12

What is Kd?

Answer 12

Equilibrium dissociation constant

Measures affinity

Question 13

What does high affinity mean?

Answer 13

A much greater tendency to bind to the receptor (large K1) relative to its dissociation from the receptor (small K-1)

Question 14

What does Kd equal?

Answer 14

K-1 / K1

Question 15

How is true affinity determined?

Answer 15

By binding-dose relationships

Question 16

What is potency?

Answer 16

Elicit a response by binding to a critical number of receptors at low concentration (high affinity) compared with other drugs acting on the same system with lower affinity.

Question 17

What does potency depend on?

Answer 17

Affinity of drug
Efficacy of drug
Receptor density
The efficiency of stimulus-response mechanisms used.

Question 18

The lower the EC50 value…

Answer 18

The greater the potency

Question 19

When are Kd and EC50 equal?

Answer 19

The linear relationship between receptor occupation and biological effect

Question 20

Spare receptors:

Answer 20

Many receptors can amplify signal duration and intensity.
Only a fraction of total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell

Question 21

What does efficacy describe?

Answer 21

The ability of an agonist to activate a receptor. (EG to evoke an ‘action’ at the cellular level)

Question 22

What is efficacy?

Answer 22

When an agonist binds to a receptor, this includes a conformational change that sets off a chain of biochemical events (an ‘action’)

Question 23

Full agonist (high efficacy)

Answer 23

Produces a maximum response while occupying only a small percentage of receptors available.

Question 24

Partial agonist (low efficacy)

Answer 24

Unable to produce a maximum response even when occupying all the available receptors

Question 25

Examples of partial agonists

Answer 25

Varenicline
Tamoxifen
Aripiprazole

Question 26

Varenicline

Answer 26

Nicotine receptor partial agonist for smoking cessation

Question 27

Tamoxifen

Answer 27

Estrogen receptor partial agonists for use in estrogen-dependent breast cancer

Question 28

Aripiprazole

Answer 28

Antipsychotic, partial agonists at selected dopamine receptors

Question 29

Inverse agonists

Answer 29

Have a higher affinity in AR state than AR* state.
Many classical competitive antagonists display inverse agonist activity.
~85% of competitive antagonists are actually inverse agonists.

Question 30

Examples of inverse agonists

Answer 30

Cimetidine (H2)
Pirenzepine (M2)
Atropine (M)

Question 31

Positive allosteric modulators (PAM)

Answer 31

Not active alone but increase affinity and/or efficacy of endogenous agonist

Question 32

Examples of Positive allosteric modulators (PAM)

Answer 32

Diazepam
Propofol
Isoflurane

Question 33

Negative allosteric modulators (NAM)

Answer 33

Not active alone but decrease affinity and/or efficacy of endogenous agonists.

Question 34

Examples of Negative allosteric modulators (NAM)

Answer 34

mGluR5 dipraglurant

Question 35

Desensitization of receptors

Answer 35

The effect of the drug reduces with continual/repeated administration. (Termed tachyphylaxis)