Prodrugs

What are prodrugs? Why are they used? What are the main requirements of prodrugs?

For the various categories of problems that were solved using prodrugs (posted on the
website) you should be able to explain what the problem was, what characteristic of the
structure caused the problem, what was the change made, how did it solve the problem, and
how was the prodrug converted back to the drug. You do not have to know the structure of
the drug (that will be given), but given the structure of the drug, you should be able to draw
the structure of the prodrug and show the modification that was made.

Prodrugs sample questions

1. Hexamine, shown below, is useful for treatment of urinary tract infections. Explain why it
works.
N

N
N

hexamine

2. The neurotransmitter dopamine can help in the treatment of Parkinsons disease, however,
dopamine itself does not cross the blood brain barrier easily because it is too polar. The
prodrug levodopa, which was developed to circumvent this problem, was even more polar!
Why does it work?
HO

COOH

HO
H2N

NH2

HO

HO
Dopamine

Levodopa

3. The antibiotic chloramphenicol shown below has a bitter taste. This taste problem was
overcome by making a prodrug. What was the change made in the prodrug and why did it
solve the problem?
OH

O2N
H

OH

Cl

N
H
Cl

4. Foscan, is a chlorin photosensitizing agent, that is under clinical trial for a treatment of a
number of cancers. Explain how it works.

HO

NH

OH

HN

HO

OH
Foscan

5. What are prodrugs? Why are they used? What properties must they have?
6. Give examples to show how a prodrug approach was used to address any two of the following
issues: For full credit you have to draw structures of the drug, state the problem with the drug,
draw the structure of the prodrug, and explain how this approach solved the problem.
1.
2.
3.
4.

Prolong the activity of the drug.

Mask the toxicity of the drug.
Improve water solubility.
Target the drug to a specific site.

Receptors and Drug Design

What are the various kinds of bonds that lead to the binding of a drug to a receptor?
Discuss the characteristics of each (you have to know the example and mechanism of
action of phenoxybenzamine covalent bonding).

Dose-Response Relationships: What are dose-response relationship plots? Why is the

response vs drug dosage plot not a straight line? Why is response usually plotted against
log(drug concentration)? Given a dose response plot you should be able to identify the
relative values of efficacy and potency of drugs, and given the relative efficacy and
potency of drugs you should be able to describe them in a plot.

Signal Transduction: What is signal transduction? What are the advantages of signal
transduction? What are the typical consequences of signal transduction?

List the main classes of receptors. For the five different classes, you have to know the
main characteristics including the following (all classes may not have all of the
following):
Structural characteristics (including schematic diagrams).

Mechanism of action.
Relative speed of response and the reason for this fast or slow response.
Duration of response (short-lived or long lasting).
Examples of ligands that bind to these receptors.
Typical systems controlled by these receptors.
Names of important proteins involved (if any).

What do the following terms mean: affinity, agonists, antagonists, ligands, efficacy,
potency, intrinsic activity, signal transduction?

Why do cells have spare receptors? What are the 3 ways in which cells alter receptor
function in order to adapt to treatment with agonists/antagonists.

Cells adapt receptor function differently to chronic treatment with a drug depending on
whether the drug is an agonist or an antagonist. Which adaptation is more dangerous with
respect to stopping the treatment? Why?

Drug Design Through Enzyme Enhibition

Why are enzymes a difficult target for drugs?

Describe, using equilibrium equations, the mechanism of action of enzymes. Which step
is usually the slow or rate-determining step?

What are the two main kinds of inhibitors (reversible and irreversible)? What are the
main characteristics of each? Why do reversible inhibitors sometime look like irreversible
ones? How do you prove whether they are reversible or irreversible?

What are the two kinds of reversible inhibition (competitive and non-competitive)?
Explain each in terms of (a) equations, and (b) schematic drawings. What are the
characteristics of each? What is the effect of saturating substrate on each? Why?

Which class do most rationally designed and clinically useful enzyme inhibitors fall into?
Why? What are the problems with designing non-competitive inhibitors?

Give 2 examples of reversible enzyme inhibition. Draw structures to show the

mechanism of inhibition (HIV-RT inhibitor, AChE inhibitor).

What are the two types of irreversible enzyme inhibitors? What are their main
characteristics? What kind of functional groups do they usually have? What kind of
interaction do they usually have with receptors? Why are they not very useful as
therapeutics?

Give examples active site directed irreversible inhibitors, i.e. affinity labels (TPCK,
TLCK). You should be able to explain their mechanism of action and state what enzymes
they are specific for.

What are mechanism based irreversible inhibitors. How are they represented by
equilibrium equations? Why are they called suicide inhibitors? What are the requirements
for a drug to be called a suicide inhibitor? Give an example of a suicide inhibitor and
explain with structures the mechanism of action.