Drug Receptor Interactions

Question 1

Describe drug receptor interactions

Answer 1

A specific protein that recognizes a ligand leading to the formation of a ligand receptor complex that initiates a series of biochemical consequences leading to a biological response
There are usually endogenous ligands for every receptor

Question 2

What’s an orphan receptor?

Answer 2

When we don’t know the endogenous ligand for a receptor is called an orphan receptor

Question 3

What makes a receptor a receptor?

Answer 3

Binding is specific, sometimes sterospecific (there is an endogenous compound a neurotransmitter, hormone, etc. that binds to the receptor in a specific way; compounds with similar structure will often bind to the same receptor)
There is a finite binding capacity for receptors (there is a limited number of receptors and binding can be saturated, i.e., all receptors may be occupied)
There is a cause an effect relationship between ligand binding and biological response
Affinity of binding is high
Receptors are tissue specific (i.e., they are in the tissues that need to respond to the ligand)
Ultimately the ligand acts as a chemical signal that produces the biological response at a specific tissue

Question 4

What forces do drugs use to bind receptors?

Answer 4

Dispersion forces (for protein interactions dispersion forces are referred to as hydrophobic interactions)
Hydrogen bonding
Ionic
Ion dipole

Question 5

How can we determine a relationship between the binding of a receptor and the biological response?

Answer 5

We can assume that there is some relationship between the number of drug-receptor complexes and the magnitude of biological response

Question 6

What is the receptor occupancy theory?

Answer 6

If we make the assumption that the magnitude of the biological response is directly proportional to the amount of receptors that are bound with drug, we can show that the effect of a drug is related to the fraction of bound receptors. Assumptions: maximum biological effect is only reach when all receptors are bound; this process follows the laws of mass action

Question 7

What is Kd?

Answer 7

The equilibrium dissociation constant . It is unique for each receptor and ligand. It is a measure of how the equilibrium is displaced to free D or free R

Question 8

What does a small Kd represent?

Answer 8

A small Kd means there is more DR and therefore more biological response, which indicates tight binding. Many drugs have binding sites between 1x10^-9 to 1x10^-6 M

Question 9

What is Ka?

Answer 9

1/Kd. It is the the affinity constant. It’s units are L/mol. It is somewhat more intuitive in that the higher the affinity constant, the tighter the binding

Question 10

What is the advantage of Kd?

Answer 10

If the receptor has a Kd of 1 uM, we know that a 1 uM [drug] will produce half maximal receptor binding

Question 11

What is intrinsic activity?

Answer 11

According to the receptor occupancy theory, the effect is proportional to the amount of receptor complexes. The instrinic activity (alpha) or efficacy is a constant of proportionality which measures the ability of the drug to produce an effect by forming a drug receptor complex. Alpha is independent of Kd

Question 12

What is ED50?

Answer 12

ED50 is the dose needed to achieve half maximal response. The ED50 of a drug is its potency; the lower the ED50, the less drug needed to get the maximal response

Question 13

What more important: potency or effect?

Answer 13

Potency is not as important as clinical effect. A drug could have a high potency but a small effect, whereas a low potency drug could have a great effect

Question 14

If Kd and ED50 are different, why do they have the same values?

Answer 14

They have the same values in receptor occupancy theory because we defined the effect as being directly proportional to receptor binding and defined maximum effect as being achieved when all receptors are bound

Question 15

What is an agonist?

Answer 15

Agonists bind to receptors and have affinity for the receptor and have intrinsic activity efficacy
Most receptors have endogenous agonists
Drugs that bind to the receptor and have intrinsic activity are agonist
Drugs that bind to the receptor and have intrinsic activity are agonists

Question 16

What is a full agonist?

Answer 16

A full agonist binds to the receptor and is capable of producing the same maximal response as the endogenous agonist

Question 17

What is a partial agonist

Answer 17

A partial agonist can bind to the receptor but produces a smaller maximal response. It therefore has a lower intrinsic activity than a full agonist which is capable of eliciting a maximal response

Question 18

What is an antagonist?

Answer 18

Antagonists bind to receptors and have affinity for the receptor but have no intrinsic activity. Drugs that bind to the receptor and have intrinsic activity are agonist
Most receptors have endogenous agonists but a drug can be an antagonist or an agonist depending on if it has intrinsic activity

Question 19

What is the spare receptors theory?

Answer 19

It is frequently found that for the same drug Kd > ED50. This means that maximal effect is achieved without bind all receptors. This phenomenon is called spare receptor theory. This usually happens when there are a series of biochemical events that transmit the signal of receptor bind across the cell membranes. There is a potential for signal amplification during these steps which means that not all receptors are needed to achieve the maximal response

Question 20

What are the more important types of antagonism?

Answer 20

Competitive antagonists

Non-competitive antagonists

Question 21

How do competitive antagonists work?

Answer 21

Competitive antagonists often have similar shapes to the agonist and have definition to fit into the agonist binding site. Therefore A cannot bind to the receptor if D is already bound and D cannot bind if A is already bound

Question 22

How does competitive antagonists affect Kd?

Answer 22

It increases the apparent Kd or decreases affinity

Question 23

How does competitive antagonists affect ED50?

Answer 23

Efficacy is the same but ED50 is higher

Question 24

How can competitive antagonists be overcome?

Answer 24

With more agonist

Question 25

How do noncompetitive antagonists work?

Answer 25

They do not bind to the same site as the agonist. They therefore can be structurally quite different. As they do not compete for the same binding site, D has the same affinity for the receptor even if A is bound. Likewise can bind to or inhibit the empty receptor of the drug receptor complex effectively reducing the pool of receptors

Question 26

How does noncompetitive antagonists affect n?

Answer 26

There is an apparent reduction in the number of receptors

Question 27

How does noncompetitive antagonists affect Kd?

Answer 27

There is not change in Kd

Question 28

How does noncompetitive antagonists affect ED50?

Answer 28

There is no change in ED50 (there is no competition for binding)

Question 29

If an antagonist binds to the same site as a drug, how can it be noncompetitive?

Answer 29

Some antagonists bind to the receptor and do not dissociate. This might be because the affinity is very high or A covalently attaches to and inactivates the receptor. Int these cases, the antagonists are always noncompetitive even if antagonist binds to the same site as the agonist. This has the effect of reducing the pool of viable receptors reducing n and Emax while not effecting Kd or ED50