Drug-Receptor Interactions

Question 1

What is the importance of understanding receptors?

Answer 1

• the pharmaceutical industry and drug development
• physiology and endogenous receptors
• chemical toxicity
• viral toxicity

Question 2

Describe GPCRs and ion channel receptors.

Answer 2

Their structure is quite similar. They are both pores in the cell membrane. Ligand-gated ion channels have binding domains, while GPCRs have that and G-protein coupling domains holding them together.

Question 3

Describe GPCRs and ion channel receptor transduction.

Answer 3

In ligand-gated ion channels, when the receptor is activated, ions are brought into the cell, causing hyper-polarisation or depolarisation of the cell, which leads to cellular effects. This happens in milliseconds.
In GPCRs, when the receptors is activated, G proteins activate a second messenger release, which leads to Ca2+ release, protein phosphorylation and other reactions. G proteins also activated an ion channel, bringing ions into the cell, which causes a change in cell excitability. This takes a few seconds.

Question 4

What is an agonist?

Answer 4

It is a drug that binds to a receptor and elicits a biological response.

Question 5

What is an antagonist?

Answer 5

It is a drug that blocks the action of an agonist compound: commonly by binding to a receptor without eliciting a biological response.

Question 6

What is a partial agonist?

Answer 6

It is an agonist drug that produces a biological effect, but never the maximal of which the tissue is capable (partial agonists possess antagonist properties).

Question 7

What is an inverse agonist?

Answer 7

It is an agonist that produces an opposing biological response to that are observed by a full agonist.

Question 8

What is affinity?

Answer 8

It is the ability of a drug molecule to bind to a receptor site.

Question 9

What is efficacy?

Answer 9

It is the ability of a drug to elicit a biological response from a drug receptor interaction.

Question 10

What are the different types of bonding, and are they reversible?

Answer 10

• Hydrogen bonding (reversible)
• Ionic bonding (reversible)
• Van der Waals forces (reversible)
• Covalent bonding (non-reversible)

Question 11

What determines drug affinity?

Answer 11

The reversible binding of an agonist to a receptor is governed by the Law of Mass Action, which states that the rate is dependant on the concentration of reactants involved.

Question 12

What does the Law of Mass Action predict?

Answer 12

• If we have a low concentration of the agonist and lots of free receptors, then there will be few AR interactions.
• If we increase the agonist concentration, we will have more AR interactions, so the reaction will be driven to the right.
• If we continue increasing the agonist concentration, and now there are few free receptors, the reaction reaches its maximal.

Question 13

What is the equilibrium constant (Ka)?

Answer 13

It is when 50% of receptors are free and 50% are bound to agonists. Each drug has its own Ka value.
A smaller Ka means that the agonist has a greater AFFINITY for the receptor (it binds more) that a drug with a higher Ka value.

Question 14

What are the ‘measurements’ of efficacy?

Answer 14

a) threshold concentration (found at the beginning of the sigmoidal saturation plot)
b) EC50: effective concentration, giving 50% of the biological response (found when you take half of the maximal concentration and extrapolate)
c) maximal concentration (at the point when the plot completely saturates)

EC50 is used to compare drug potency (determined by affinity and efficacy)

Question 15

What are the efficacies for the different agonists?

Answer 15

• FULL AGONIST: full efficacy
• PARTIAL AGONIST: less efficacy
• ANTAGONIST: no efficacy

Question 16

Describe partial agonists.

Answer 16

Partial agonists are present at receptors; they have a HIGH AFFINITY but LOW EFFICACY. It reduces withdrawal symptoms, such as addictive ‘highs’.

Question 17

Describe competitive antagonism.

Answer 17

Receptors will only bind to either agonists (A) or antagonists (Ant). This means that they must compete for the same binding site. They both bind reversibly. The reaction is now dependant on two equilibrium constants, KA and KAnt.
If KAnt is greater than KA, then Ant has a greater affinity for receptors than A. This means that [A] must increase to overcome Ant binding to the receptors.

Question 18

Describe the effect of competitive antagonism on the saturation plot.

Answer 18

In the presence of the Ant concentration, the effect of the curve is shifted to the right. (The shift to the right is linear to [Ant]).
The linear part of the curves are parallel, and the same maximal is obtained.

Question 19

Describe non-surmountable antagonism.

Answer 19

With non-surmountable antagonism, we have a reduced slope and a depressed maximum when we add the antagonist to the equation.
This happens by either NON-COMPETITIVE ANTAGONISM (where the antagonist binds to a different site from the agonist) or IRREVERSIBLE ANTAGONISM (where the antagonist binds irreversibly to the receptor, reducing the number of free receptors).