Lecture 3- How drugs bind to their targets

Question 1

Where do agonists bind?

Answer 1

Orthosteric binding site

Question 2

Where do competitive inhibitors bind?

Answer 2

Also the orthosteric site

Question 3

Where do allosteric modulators bind?

Answer 3

Allosteric sites

Question 4

What is the difference between agonism and antagonism?

Answer 4

• Agonism refers a substance/drug binding to a receptor and influences its activty
• Antagonism refers to a substance/drug binding to a receptor an influencing its response to an agonist.

Question 5

Agonists bind to a receptor and usually ____ the activity of a receptor. Inverse agonist ____ the activity of the receptor

Answer 5

increase;reduce

Question 6

What are the 2 types of antagonists?

Answer 6

competitive and non-competitive

Question 7

A ____ antagonist requires a higher concnetration of agonist to generate a given response, but agonist efficacy is not changed. They will shift the apparent potency to the agonist and EC50 will be ____ when it is present.

Answer 7

competitive; higher

Question 8

A ____ antagonist reduces agonist efficacy but no effect on its potency. It will have no shift in its apparent potency and the EC50 will be ____ but you will have a reduction in the efficacy and this is an insurmountable reduction

Answer 8

non competitive; same

Question 9

A competitive antagonist occupies the ____ binding site as the agonist but does not eflicit a biological response.

Answer 9

same

Question 10

At ____ enough agonist concentrations, the antagonist is displaced and maximal ____ can be achieved; sometimes called a ____ antagonist

Answer 10

• high
• efficay
• surmountable

Question 11

The ____ inhibitor you have, the ____ agonist you need.

Answer 11

more;more

Question 12

Since a competitive antagonist ____ generate a biological effect on its own, it can be difficult to measure how antagonists interact with receptor.

Answer 12

does not

Question 13

What is illustrated based on the dose ratio or the concentration?

Answer 13

Schild plot

Question 14

What is a dose ratio

Answer 14

indicates the fold increase of the agonist needed to achieve the same response at a given concentration of antagonist

Question 15

____ concentrations of antagonist require a ____ concentration of agonist to generate a maximal response

Answer 15

larger; larger

Question 16

Competitive antagonists exhibit a ____ schild plot

Answer 16

linear

Question 17

The x-intercept is sometimes refered to as the pA2 or pKi and reflects the ____ of the antagonist

Answer 17

potency

Question 18

The more strongly binding the antagonist is to the receptor, the ____ the concentration will be, the more ____ shifted it will be on the X-axis.

Answer 18

smaller; left

Question 19

The more weakly binding the antagonist is to the receptor, the more shifted it is to the ____ on the curve and therefore, the ____ antagonist is needed to generate a big shift in the EC50 of the agonist

Answer 19

right;more

Question 20

Competitive antagonists shift the apparent potency of the agonist but ____ chance the efficacy.

Answer 20

do not

Question 21

As you add more competitive antagonist, you shift the cocnentration response curve more and more to the ____. The more agonist you have, the ____ antagonist you need to inhibit. The more antagonist you have, the ____ agonist you need to relieve the inhibiton.

Answer 21

right; more; more

Question 22

True or False: An antagonist that leads to a small shift in the EC50 is weakly potent, it binds less strongly to the agonist

Answer 22

True

Question 23

Provide an important example of a competitive antagonist (think opioid overdose)

Answer 23

Naloxone (‘Narcan’) is a competitive non-specific opioid receptor antagonist used as an antidote for opioid overdoses

Question 24

How can partial agonists act as antagonists?

Answer 24

By competing for binding with the full agonist - lead to decreased overall response

Question 25

____ ____antagonism is when an antagonist binds irreversibly to the orthosteric site by forming a covalent bond and can’t be displaced resulting in ____ efficacy.
Also known as non-competitive antagonism

Answer 25

Irreversible competitive; reduced

Question 26

What is a non-competitive antagonist and where do the non-competitive antagonists bind?

Answer 26

• A non-competitive antagonist will reduce agonist efficacy but NOT its potency (no shift in EC50)
• No matter how much agonist is administered, a full effect is not observed.
• It binds to the Allosteric site

Question 27

Binding of the non-competitive antagonist might prevent ____ of the agonist bound receptor

Answer 27

activation

Question 28

1. What are positive allosteric modulators (PAMS)?
2. Are smaller concentrations or larger concentrations prefered to elicit a good response in presence of a PAM?

Answer 28

• They are drugs that interact with the allosteric site and increase to ability of the agonists to activate the receptor
• Smaller concentrations of the agonists are required to elicit a good response in the presence of a PAM

Question 29

Gaba receptors are ____ receptors. When they are open, they have a ____ effect on our brain. They prevent neurons from firing in our brain. They also prevent seizures, anxiety or hyperstimulation if taken at a ____ to ____ dose. When an individual abuses alcohol chronically and then stop, they have withdrawal symptoms such as hallucinations, extreme anxiety, seizures and shaking tremors. They happen because chronic use of alcohol cause a ____ of gaba receptor levels in the brain

Answer 29

• inhibitory
• suppressive
• low-medium
• reduction

Question 30

What is another example of a positive modulator of Gaba receptors?

Answer 30

• Benzodiazepines; it has an EC50 and the more GABA you add, the higher the activity of the channels.
• Benzodiazepines act to shift the concentration response to smaller concnetrations of the agonist.

Question 31

Waht method is used to evaluate pharmalogical properties of an antagonist?

Answer 31

Schild plot

Question 32

What does Kd represent in the equation below?

Answer 32

• It is the dissociation constant which is used to refer to the potency of direct binding of a drug to a receptor
• it gives you 50% of the full occcupancy of the receptors bound by the ligand

Question 33

Why can there be a mismacth between binding and effect?
(use GCPR as an example)

Answer 33

• there are more receptors present than are required for activation of a full biological effect.
• i.e., activation of a single g-protein can lead to many cAMP molecules and activation of many effector protein. Due to the amplifying effects, there is not a direct relationship between agonist binding and biological effect.