Download Topic guide 9.1: Drugs and receptor sites

Unit 9: Medicinal Chemistry
.
91
Drugs and receptor
sites
Drugs used in medicine may alter the metabolism of cells and organs in
the human body, or they may kill or inactivate pathogens such as bacteria,
viruses and fungi. Regardless of their effect, all drugs work by binding to
specific target molecules within the organism. These target sites can be of two
different types, enzymes or receptor sites.
In this unit you will look at how drugs bind to these target sites and start to
understand how this affects the metabolism.
On successful completion of this topic you will:
•• understand the role of enzymes and receptors as drug targets (LO1).
To achieve a Pass in this unit you need to show that you can:
•• explain the role of enzymes and receptors as drug target sites (1.1)
•• explain drug-receptor binding interactions (1.2)
•• distinguish between competitive and non-competitive enzyme
inhibition (1.3)
•• explain the relationship between receptors and drug affinity, efficacy and
potency (1.4).
1
Unit 9: Medicinal Chemistry
1 Enzymes as drug targets
Enzymes
Enzymes are macromolecules, usually proteins, which act as biological catalysts –
they create a new pathway that allows a reaction to occur many times faster than
the uncatalysed reaction.
Drug case study
The action of many antibiotics is a result of the antibiotic drug targeting specific enzymes in the
metabolism of bacteria. For example, penicillin (discussed in detail in Topic guide 9.4, section 1)
acts by binding to an enzyme in bacteria that plays a key role in the construction of the bacterial
cell wall.
Mechanism of enzyme action
Link
You can remind yourself of the role
that some specific enzymes play
in living organisms by referring to
Unit 1: Biochemistry of Macromolecules
and Metabolic Pathways.
Knowledge of the way in which enzymes work is important in the design of drugs
that target enzymes.
Enzymes act on specific molecules called substrates that bind to a region of the
enzyme known as the active site (or binding site) to form an enzyme substrate
complex, e.g. as shown in Figure 9.1.1. Only specific substrates can fit and bind
to the active site because the substrate and active site have complementary
shapes and charges; drug molecules are often designed to mimic the shape of the
substrate molecule.
Figure 9.1.1: Structure of an enzyme
showing the active site, substrate
and non-competitive binding site.
Enzyme
Substrate
Active site
Non-competitive inhibitor
Non-competitive binding site
Inhibitors
Key term
Inhibitor: A molecule that reduces
the activity of an enzyme.
9.1: Drugs and receptor sites
The ability of drugs to affect enzyme activity, and hence alter metabolism in cells,
is due to their ability to act as inhibitor molecules.
Inhibitors can be classified as non-reversible or reversible.
•• Non-reversible inhibitors: these bind strongly to the active site but are not
converted into product molecules.
•• Reversible inhibitors, which are of two types:
•• competitive inhibitors – these have similar structures to substrate
molecules and can bind to the active site in a similar way. The inhibitor and
the substrate are competing for the active site and hence inhibition can be
reversed by increasing substrate concentration.
•• non-competitive inhibitors – these bind to a second binding site (often
called an allosteric site). The binding decreases enzyme activity by
producing a conformational change in the enzyme structure. Inhibition
can be reversed only by reducing the inhibitor concentration.
2
Unit 9: Medicinal Chemistry
Table 9.1.1: Examples of drugs
that act as inhibitors.
Drug
Some inhibitors act by a mixed mechanism, bonding to both the active and
allosteric site.
Table 9.1.1 shows some examples of drugs that operate as inhibitors.
Use
Type of inhibition
Description of effect
Aspirin
Analgesic (pain relief)
Non-reversible
Prevents the binding of arachidonic acid to a cyclooxygenase
(COX) enzyme, necessary for the formation of prostaglandins
Methotrexate
Cancer treatment
Competitive
Competes with tetrahydrofolate for the active site of
dihydrofolate reductase, necessary for nucleotide synthesis
Fluoride
Anti-bacterial action on oral bacteria
(added to toothpaste and some
water supplies)
Non-competitive
Binds to a site on the enolase enzyme that converts
2-phosphoglycerate to phosphoenolpyruvate during glycolysis
Activity
Link
Use research to find out more about the effect of each of the drugs in Table 9.1.1. You should
be able to explain how the described effect shown above might link with the way in which these
drugs are used (for example, why preventing nucleotide synthesis would be useful in a drug
designed to treat cancer).
You will find more information about
methotrexate and its mechanism of
action in Topic guide 9.4, section 1.
Other receptor sites
You will find out more about the way in which drugs interact with other targets,
such as receptor sites on the surface of cells and ion-channels, on pages 9–12 of
this topic guide.
Checklist
You should now be familiar with the following ideas about drugs and enzymes:
 most drugs work by binding to specific target sites
 the bonding of drugs to target sites produces changes in the metabolism of human cells or in
pathogenic organisms
 enzymes are important examples of substances with active target sites
 an enzyme has an active site that enables it to bind to a substrate molecule
 an enzyme can be inhibited by a molecule or ion that binds to the active site or another site on
the enzyme
 types of inhibition include irreversible, reversible competitive and reversible non-competitive.
2 How do drugs bind to receptor sites?
Enzymes and most other receptor sites are proteins. They contain polypeptide
chains that consist of amino acid residues bonded together by peptide links.
There are 20 different amino acids found in protein molecules; they differ in the
nature of the side group and these side groups are responsible for the interactions
that bind the drug molecule to the receptor site.
9.1: Drugs and receptor sites
3
Unit 9: Medicinal Chemistry
Types of drug-receptor binding interactions
Drug-receptor binding makes use of a range of types of chemical bonding: ionic,
hydrogen-bonding, Van der Waals interactions and covalent bonding. Drug
molecules that bond to receptors in this way are often described as ligands.
Various types of protein-ligand bonding are shown in Figure 9.1.2.
NH3+
Ionic
O–
Hydrogen bonding
C
Figure 9.1.2: This diagram illustrates
how amino acid side groups are
involved in forming various different
types of bonds to ligand molecules.
O
δ+
H
CH2
CH2
N
H
C
O
δ–
O
Van der Waals
Cu2+
CH2
C
H
H
N
C
H
H
O
CH2
C
Link
If you are unfamiliar with different
types of chemical bonds you can find
more information in Unit 5: Chemistry
for Applied Biologists.
N
C
H
H
:
O
Covalent
(CH2)5
O
NH2
O
C
N
C
C
H
The folding of the protein chain that creates the shape of the active site allows
specific side groups to come into close alignment with groups in the substrate and
form bonds (see Figure 9.1.3 for an example).
Figure 9.1.3: Adrenaline bonds
to its receptor site using a range of
binding interactions; the folding
of the protein chain in the receptor
site allows several different amino
acid side chains to be involved.
phe290
Van der Waals
interactions
CH3
H3C
O
O
+
N
Ionic
bond
OH
–
O
O
OH
δ+
H
δ–
O
H
δ+
δ–
O
H
ser207
ser204
H
Hydrogen bonds
asp113
Functional groups involved in drug-receptor sites
Take it further
Table 9.1.2, on the following page, shows the names of amino acids as three letter abbreviations.
The full names and structures of the 20 naturally occurring amino acids can be found in standard
biochemistry textbooks or online at sites such as:
www.biochem.ucl.ac.uk/bsm/dbbrowser/jj/aastruct.html.
9.1: Drugs and receptor sites
4
Unit 9: Medicinal Chemistry
Table 9.1.2: The functional groups
present in some amino acids.
Checklist
You should now be familiar with the
following ideas about drug-receptor
interactions:
 most receptor sites are proteins
 a range of electrostatic forces exist
which permit binding between
the drug and the receptor site
 the binding involves a range of
amino acid side groups on the
surface of the receptor site.
Functional group
Amino acid residue
containing this group
Types of interactions involving
this group
–COOH (becomes COO– in
alkaline conditions)
asp, glu,
Ionic (in ionised form)
Hydrogen bonding (in unionised
form)
–NH2 or –NH–
(becomes –NH3+ or –NH2+- in
acidic conditions)
lys, arg, his
Ionic (in ionised form)
Hydrogen bonding (in un-ionised
form)
–OH
ser, tyr, thr
Hydrogen bonding
–CH3 (and longer
hydrocarbon chains)
ala, val, leu, ile, met
Van der Waals
–C6H5
phe, tyr, trp
Van der Waals
Portfolio activity (1.2)
Use a suitable source of information to find the molecular structure of a drug molecule. Look
at the functional groups in the drug molecule and suggest possible interactions that may form
between these functional groups and a protein-based receptor site. A good example to use might
be captopril, used to treat high blood pressure (see Topic 9.4 for more details). The structure of this
molecule and that of the receptor site should be easily found by searching on the internet.
3 Enzyme inhibition and drug action
Making use of different types of inhibition
You read on pages 2–3 that enzymes are the target of many drug molecules, and
that these drugs work by inhibiting enzymes.
Case study: Using different types of inhibition
During the identification and development of new drugs it will be important to establish what
type of inhibition is involved, as drugs operating by different mechanisms of inhibition may be
used in different ways. For example:
•• irreversible inhibition (e.g. in the action of aspirin) permanently deactivates an enzyme, often
at low inhibitor concentration. This could be helpful in drugs designed to target pathogenic
microorganisms or for treatment of chronic pain.
•• reversible competitive inhibition (e.g. in the action of methotrexate) is reversed when the
ratio of substrate concentration to inhibitor concentration rises. This may mean that the drug
may only be effective in high concentrations, increasing the possibility of harmful side effects.
•• reversible non-competitive inhibition (e.g. in the action of fluoride) occurs at a separate
binding site, not the active site, and hence the drug molecule may have no structural similarity
to the substrate of the enzyme. This may increase the stability of the drug as there may be no
natural pathways for their degradation. As a result the drug may need to be administered less
frequently or at a lower concentration.
9.1: Drugs and receptor sites
5
Unit 9: Medicinal Chemistry
Distinguishing between different types of reversible
inhibition
As you saw in the case study on page 5, the type of inhibition involved in the
mechanism of drug action has some important implications for how it can
be used.
This can easily be done in the laboratory by carrying out kinetic studies to find
how the rate (or velocity) of an enzyme-catalysed reaction depends on the
concentrations of substrate and inhibitor.
Michaelis-Menten plots
Experimenters can carry out investigations to measure the rate (reaction velocity,
V) of an enzyme-catalysed reaction at different concentrations.
A graph of reaction velocity against substrate concentration is known as a
Michaelis-Menten plot (see Figure 9.1.4 for an example).
Vmax
Reaction velocity (V0)
Figure 9.1.4: In a Michaelis-Menten
plot, the reaction velocity increases
with substrate concentration but
eventually reaches a maximum (Vmax)
at high substrate concentration.
Vmax/2
Km
Substrate concentration (S)
Key terms
Km (the Michaelis constant): The
substrate concentration at which
the reaction velocity of an enzymecatalysed reaction is equal to Vmax/2.
Vmax (turnover rate): The number of
substrate molecules converted into
product molecules per unit time.
The graph tends asymptotically towards Vmax because at high substrate
concentrations the enzyme is becoming fully saturated with substrate. When this
happens, the enzyme is working at maximum rate. Vmax is often expressed as the
turnover rate (number of substrate molecules converted into product molecules
per second).
Finding Vmax enables experimenters to find the value of Km (the Michaelis
constant). Km can be calculated by finding the substrate concentration at which
the reaction velocity is one-half of the maximum (Vmax/2).
The value of this constant for an enzyme is a useful measure of how well the
enzyme binds the substrate.
Applying the Michaelis-Menten model to enzyme inhibition
Laboratory investigations can be used to distinguish between the two main types
of reversible inhibition.
Reaction rate is measured at different substrate concentrations and repeated with
a range of different inhibitor concentrations.
9.1: Drugs and receptor sites
6
Activity
The effect of inhibitor molecules on
the values of Km and Vmax is helpful
to drug designers in assessing the
strength of the binding between the
inhibitor and the active site.
1 Look at graph (a). Use it to
estimate values of Vmax and Km for
the enzyme without inhibitor.
Repeat this process for the
enzyme with inhibitor.
2 Repeat the process for graph (b).
3 Check that the values you obtain
are consistent with the differences
described in the bullet list.
4 Which enzyme appears to bind
the substrate most strongly?
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
(b)
No inhibitor
With inhibitor
10 20 30 40 50 60 70
[S]/µm
Reaction velocity µm/min
(a)
Figure 9.1.5: Michaelis-Menten
plots showing the effect of different
concentrations of inhibitor for (a) an
enzyme that undergoes competitive
inhibition (b) an enzyme that undergoes
non-competitive inhibition.
Reaction velocity µm/min
Unit 9: Medicinal Chemistry
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
No inhibitor
With inhibitor
10 20 30 40 50 60 70
[S]/µm
The graphs in Figure 9.1.5 show several important differences:
•• Both graphs show that reaction rate is reduced in the presence of inhibitors.
However, in the case of competitive inhibition, the inhibition can be overcome
if substrate concentration is high enough.
•• For competitive inhibition, Vmax remains unaltered in the presence of an
inhibitor; for non-competitive inhibition Vmax decreases to a new value,
depending on the inhibitor concentration.
•• For competitive inhibition, Km increases in the presence of an inhibitor; for
non-competitive inhibition Km remains unaltered.
Lineweaver-Burk plots
Accurately measuring Km and Vmax from Michaelis-Menten plots, and hence
distinguishing competitive from non-competitive inhibition, was once very
difficult because the graph needed to be extrapolated by hand. Graph-plotting
software now avoids this problem, but a second method exists, which can be used
as an alternative.
In this method, called the Lineweaver-Burk plot (or double reciprocal plot), the
reciprocal of the reaction velocity, 1/V, is plotted against the reciprocal of substrate
concentration 1/[S].
This yields a straight line, given by the following equation:
1
1
K 1
=
+ m
V0 Vmax Vmax [S]
Comparing with the general equation for a straight line,
y = c + mx,
this suggests:
Figure 9.1.6: In a Lineweaver-Burk
plot, Km can be calculated from the
x-intercept and Vmax from the y-intercept.
1/V
Slope = Km/Vmax
•• the slope of the graph =
•• the y intercept =
1
Vmax
•• the x-intercept = –
Km
Vmax
1
Km
Figure 9.1.6 shows an example of a Lineweaver-Burk plot.
Intercept = –1/Km
Intercept = –1/Vmax
0
1/[S]
9.1: Drugs and receptor sites
7
Unit 9: Medicinal Chemistry
Case study
Key term
New drug molecules are continually being developed to act as competitive inhibitors of metabolic
enzymes. During the screening process to assess the possible use of a molecule as a drug, its
ability to bind to the active site will be assessed. Michaelis-Menten or Lineweaver-Burk plots can
be used to provide useful information about this. The Km value with and without an inhibitor
present can be measured and from these values the dissociation constant of the enzyme-inhibitor
complex, Ki as well as the IC50 value of the inhibitor. Both of these are important measures of the
binding of the inhibitor.
IC50: The concentration of the
inhibitor required to reduce enzyme
activity by one half.
1 What happens to the Km value of an enzyme in the presence of a competitive inhibitor?
2 If the IC50 value of an inhibitor is small, what does this tell you about the strength of the bond
between the inhibitor and the enzyme?
Lineweaver-Burk plots for competitive and non-competitive
inhibitors
These are shown in Figure 9.1.7, and demonstrate what you already know from
the previous section – that Km and Vmax are affected in different ways in these two
modes of inhibition. Table 9.1.3 gives a summary of the effects.
Figure 9.1.7: Non-competitive
and competitive inhibitors show
different patterns of kinetics
in Lineweaver-Burk plots.
1/V
+ Non-competitive
inhibitor
1/V
+ Competitive
inhibitor
No inhibitor
present
1/[S]
0
Table 9.1.3: Types of inhibition
No inhibitor
present
1/[S]
0
Type of inhibition
Effect on x-intercept (–1/Km)
Effect on y-intercept (1/Vmax)
Competitive
Decreases
Unchanged
Non-competitive
Unchanged
Increases
Portfolio activity (1.3)
Activity
Use ideas about how Vmax and Km
change in the presence of different
types of inhibitor to explain the
pattern in the way the intercepts
change in the Lineweaver-Burk plots.
9.1: Drugs and receptor sites
You can generate evidence for your portfolio by carrying out practical work on enzyme kinetics.
1 Select a reaction to study. It should be one where a measure of the rate of the reaction can be
obtained using the equipment available to you, and where there are known inhibitor(s).
2 Carry out suitable experiments generating data for reaction rates. Ensure that you have the
correct range of data to allow you to construct suitable plots. Alternatively, secondary data can
be obtained from websites or textbooks.
3 Describe what is meant by competitive and non-competitive inhibition.
4 Plot suitable graphs that will enable you to identify what type of inhibition is operating in the
reaction.
5 Explain how your graphs enable you to identify the type of inhibition.
8
Unit 9: Medicinal Chemistry
Take it further
There are several suitable books or websites that show you how the Michaelis-Menten
equation is derived and discuss the assumptions in the way it is used. Try Biochemistry (Berg,
Tymoczko and Stryer, 2002), Chapter 8, p200–205 and p221–222, which can be searched online at
http://www.ncbi.nlm.nih.gov/books/NBK22430. This chapter also includes some problems with
data that you could use to practise for your portfolio work or as data for the portfolio exercise.
Checklist
You should now be familiar with the following ideas about enzyme inhibition and drug action:
 data from kinetic investigations of enzyme-catalysed reactions can be used to distinguish
between different modes of inhibition
 reaction rate can be plotted against [S] to obtain a Michaelis-Menten plot
 Michaelis-Menten plots are used to obtain values for Km and Vmax
 competitive inhibitors increase Km but do not affect Vmax
 non-competitive inhibitors do not affect Km but decrease Vmax
 double reciprocal plots (Lineweaver-Burk plots) provide an alternative way of deriving values
of Km and Vmax and enable competitive and non-competitive inhibition to be distinguished.
4 Receptors and drug action
In the previous section you read about how enzymes are used as targets for drugs;
the physiological effect is caused by the inhibition of these enzymes.
In this section you will find out more about the other main receptor types used as
drug targets and some of the implications for health professionals involved in the
prescribing and administration of these drugs.
Types of receptors
There are four main types of receptors that act as drug targets:
•• ion channels, which can open or close in response to the drug binding
•• enzyme-coupled receptors – receptors on the outer surface of cell membranes
which can activate enzymes on the interior surface of the membrane
•• G protein-coupled receptors – receptors on the outer surface of cell
membranes that can activate G proteins on the interior surface of the
membrane. These in turn activate enzymes, which produce chemical
messengers such as cyclic AMP
•• receptors within the cell, for example sites in the nucleus which control
transcription.
Key term
Ligand: a substance that binds to
a biological molecule (such as a
protein) to form a larger complex.
These receptor molecules all have a specific role in the control of cellular processes
and there are naturally occurring ligands that bind to the receptor molecule,
forming a ligand-receptor complex. Ligands usually have a complementary
structure to the receptor site, so this is a very similar situation to the enzymesubstrate mechanism discussed in the previous section.
Many drug molecules act as ligands for a range of receptor sites, which explains
the wide range of physiological effects produced by some drugs.
9.1: Drugs and receptor sites
9
Unit 9: Medicinal Chemistry
Signal transduction
Key term
Signal transduction: a mechanism
that converts a stimulus signal on
the surface of a cell into a specific
response within the cell.
Figure 9.1.8: The mechanism
of signal transduction.
Signal
Ligand
Receptor
Membrane
Two of these types of receptor involve signal transduction. In these cases the
effect of a drug on an enzyme is not a direct one. The drug molecule may bind to a
receptor site (the recognition site) outside the cell – if that receptor site is linked in
some way to an enzyme system (the effector) within that cell, then a new, specific
response may be created within it. Figure 9.1.8 shows this in diagrammatic form.
Take it further
In How Drugs Work (McGavock, 2010), p36, the transduction process is described using the analogy
of a doorbell; the bell button is the receptor receiving the external signal, which is then transduced
into an entirely different signal by the effector (the chiming of the bell) inside the house. This
helpful image is typical of the accessible writing in this book, which gives excellent, clear coverage
of the action of drugs.
Transduction
Activity
Interior
of cell
Effector
Response
Use suitable references to research the transduction pathway involving the G protein, adenylate
cyclase and cyclic AMP. Find some examples of drugs that affect this pathway and, for one of these
drugs, briefly describe how it does this.
Agonists and antagonists
If a drug produces the same response as that of the natural ligand when it binds to
a receptor site, it is known as an agonist.
In other cases, a drug molecule may bind to the receptor site without causing a
response. If, by binding in this way, the drug prevents further ligands binding (by
blocking the site or causing a conformational change) then the drug molecule is
known as an antagonist.
Table 9.1.4 shows an example of each type of drug.
Table 9.1.4: Examples of drugreceptor interactions
Drug name
Used to treat
Mechanism of action
Agonist or
antagonist
Nifedipine
Angina,
hypertension
Binds to ion channel protein on surface of
smooth muscle cells, preventing calcium
ions from crossing membrane and altering
electrical potential of cell
antagonist
Salbutamol
Asthma
Binds to recognition site on surface of
membrane. This activates the G protein on the
internal surface, stimulating cAMP production
(see Activity above)
agonist
Affinity and efficacy
When a medical professional is taking decisions about suitable dose levels of a
drug there are several very important aspects of drug biochemistry to take into
account.
Some of these are related to the way in which drugs are absorbed and broken
down by the body.
9.1: Drugs and receptor sites
10
Unit 9: Medicinal Chemistry
Figure 9.1.9: The effect of a drug does
not increase linearly with concentration.
100
Drug A
(full agonist)
0
Explaining patterns of drug effect
Drug B
(partial agonist)
50
One key factor is related to how the effect of the drug varies with drug
concentration. This is not a linear relationship, as shown in Figure 9.1.9. Notice in
this diagram how a logarithmic scale is used for the x-axis.
–12 –11 –10 –9 –8 –7 –6 –5
lg (concentration of drug in M)
Link
You will learn more about
pharmacokinetics – the study of the
absorption and breakdown of drugs
in the body – in Topic guide 9.2.
The effect of both of these drugs increases as the concentration of the drug
increases because more drug-receptor complexes are formed. However, agonist
drugs compete with the natural ligand for the receptor site so the percentage of
binding sites occupied by drug molecules will always be slightly less than 100%
even at very high drug concentrations. This explains why the graph levels off to
a maximum. The concentration at which this happens depends on the relative
affinity of the receptor for the drug and the natural ligand.
In the case of Drug B, the maximum effect is never approached. This is because the
drug produces a lower level of response than Drug A – it is described as having a
lower efficacy.
The potency of the drug is therefore affected by both affinity and efficacy. Potency
is often measured by calculating the EC50 concentration (the concentration of
a drug needed to produce an effect equal to 50% of the maximum effect). For
an inhibitor molecule, this figure is known as the IC50 value and represents the
concentration needed to inhibit a biological process to 50% of its level in the
absence of an inhibitor (see the Case study for a real-life example).
Key terms
Take it further
Affinity: The strength of the
interaction between a drug and
its receptor site. Value of Kd (the
dissociation constant for a drugreceptor constant) can allow affinities
to be compared – a low value of Kd
means a high affinity.
Databases of information about the patterns of drug effects, including data relating to affinity
and potency are widely available on the internet, for example at
http://www.bindingdb.org/bind/index.jsp.
Efficacy: The ability of a drug to
produce a response once it is bonded
to a receptor site, i.e. the maximum
response achievable for a given drug.
Potency: The concentration of the
drug needed to produce an effect
at a specific level (often 50% of the
maximum possible response).
EC50: A common measure of potency
– it is the concentration of a drug
at which the effect is 50% of the
maximum possible. For a drug that
acts as an inhibitor EC50 = IC50.
Tolerance: A gradual decrease in
the reaction of a subject to a drug.
This results in an increase in the
concentration of a drug needed to
produce a given level of effect.
9.1: Drugs and receptor sites
Activity
Use the graph showing the effects of Drug A and Drug B in Figure 9.1.9 to calculate a value for the
potency (EC50 value) of each drug.
Case study
During the screening process to assess the possible use of drugs as inhibitors of enzymes, a value
of the IC50 is often calculated, either by biological assays or by computer modelling. The lower the
IC50­ value, the more likely the molecule is to be able to be used as a drug.
In Topic guide 9.3, section 1 you will see how gradually decreasing values of IC50 for BACE-1
inhibitors were used to show how the lead compound had become optimised.
Tolerance and dependency
Tolerance
Taking high doses of drugs over an extended period of time can lead to tolerance.
This means that the concentration required to produce a given level of effect will
progressively increase.
11
Unit 9: Medicinal Chemistry
Tolerance can be psychological, but there are also physiological mechanisms
that can produce it. For example, continued use of opiates such as morphine
(prescribed for relief of extreme pain) can create tolerance, possibly due to
molecules involved in signal transduction permanently altering the conformation
of receptor sites.
Take it further
Link
You will learn more about drug
degradation in Topic guide 9.2.
More details about the research into opiate tolerance can be found at
http://www.opioids.com/morphine/dependence.html
Tolerance may also be linked to an increase in the rate at which the drug is
degraded in the body.
I am a nurse in a hospice. We provide care for people in final stages of terminal illnesses, such as
cancer. The philosophy of the hospice movement is to provide an environment that maintains
the dignity of an individual while providing pain relief to make their final days as comfortable as
possible. Many patients will be able to self-medicate with morphine using oral suspensions and
this allows them to have a sense of control over their medication regimen, balancing pain relief
against their desire to stay as alert and awake as possible.
One thing that we must be aware of in use of morphine is the possibility of rapidly building up a
physiological tolerance, meaning that higher and higher doses are needed to achieve the same
level of pain relief. These higher concentrations that the patient may need to use could create
other problems such as the possible suppression of respiration. We are looking into the possibility
of prescribing additional drugs that may be able to slow the development of this tolerance. Other
issues, such as that of dependence, are of secondary importance in this end-of-life care as the
timescale for the use of morphine is, by its very nature, limited.
Dependency
Key term
Dependence: A physical or
psychological need for a drug.
In the case of opiate-based drugs, the development of tolerance often goes hand
in hand with that of dependence. Drugs such as opiates stimulate dopamine
production that, in turn, acts on the ‘pleasure’ centre of the brain, creating a
psychological craving for more when levels drop.
Portfolio activity (1.4)
Use research to find information about a drug which binds to a specific type of receptor. Good
examples could include captopril, which you encountered in an earlier activity, and dopamine.
1 Identify the type of receptor to which it binds.
2 Explain whether it is an agonist or antagonist.
3 Describe what is meant by the terms affinity, efficacy and potency and comment on any data
you can find relating to these factors.
4 Explain how tolerance and dependence arise and comment on their significance (if any) in the
use of your chosen drug.
9.1: Drugs and receptor sites
12
Unit 9: Medicinal Chemistry
Checklist
At the end of this section, you should be familiar with the following ideas:

there are four main types of receptors

drugs act as ligands, binding to these receptors

drugs can act as agonists or antagonists

the potency of a drug depends on its affinity for the receptor and its efficacy

the development of tolerance and dependence are other issues which need to be considered
by practitioners.
Acknowledgements
The publisher would like to thank the following for their kind permission to reproduce their
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All other images © Pearson Education
We are grateful to the following for permission to reproduce copyright material:
MIT OpenCourseWare for the figure 'Types of Chemical Bonds in Ligand-Receptor Interactions'
from 20.201 Mechanisms of Drug Actions, Fall 2005 by Peter Dedon and Steven Tannenbaum, MIT
OCW, Biological Engineering. Reproduced via the Creative Commons Licence; W.H. Freeman and
Company for figures 8.11, 8.36, 8.37, 8.38 from Biochemistry, 5th edition by Berg JM, Tymoczko JL,
Stryer L., copyright © 2002 by W.H. Freeman and Company. Used with permission.
In some instances we have been unable to trace the owners of copyright material, and we would
appreciate any information that would enable us to do so.
9.1: Drugs and receptor sites
13