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Samenvatting - Receptor Pharmacology (WBFA036-05)
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RECEPTOR PHARMACOLOGYSECTION 1: GENERAL PHARMACOLOGICAL PRINCIPLES
LECTURE 1-1:
Pharmacology has to do with
interactions of chemical
substances (drugs) with the
living organism. A drug is
considered a chemical, which is
applied to a physiological system
that affects its function in a
specific way. Pharmacokinetics
deals with absorption,
distribution, excretion, etc.,
whereas pharmacodynamics
deals with the drug at the active
site of the drug in the body. Pharmacology has a lot of similarities with pharmacodynamics.
Non-specific drug actions: biological effect at relatively high drug concentrations (e.g. antacids,
adsorbents, osmotic agents)
Specific drug actions: biological effect at relatively low drug concentration and have chemical and
biological specificity.
Most drug act on target proteins with high affinity to the drug.
Drugs act on target proteins:
1. Receptors
Are target molecules whose function is to recognize and respond to specific endogenous
chemical signals, such as hormones, neurotransmitters, and inflammatory mediators.
2. Ion channels
3. Enzymes
4. Carriers / transporters
Receptors and ion channels are the most commonly used target proteins.
The specificity of drug action is reciprocal, which means that individual classes of drugs bind to
discrete receptors, while individual receptors recognize only discrete classes of drugs. High specificity
by high affinity. However, no drug are completely specific in their action. Side effects may occur at
relatively high drug concentrations, due to binding to other targets (receptors) with lower affinity.
Distinction between drug binding and receptor
activation:
Agonist: receptor occupation leads to biological
response
Antagonist: receptor occupation does not lead to
response and prevents the effect of an agonist, mostly
by preventing it from binding
A combination of an agonist versus an antagonist is the
agonist acetylcholine and the antagonist atropine.
,Drug-receptor binding:
Rate of forward reaction = 𝑘+1 𝑥𝐴 (𝑁𝑡𝑜𝑡 − 𝑁𝐴 )
Rate of backward reaction = 𝑘−1 𝑁𝐴
𝑘+1 𝑥𝐴 (𝑁𝑡𝑜𝑡 − 𝑁𝐴 ) = 𝑘−1 𝑁𝐴
Fractional occupancy: 𝑃𝐴 = 𝑁𝐴 ∕ 𝑁𝑡𝑜𝑡
𝑁𝐴 𝑥𝐴
𝑃𝐴 = =
𝑁𝑡𝑜𝑡 𝑥𝐴 + 𝐾𝐴
This last formula is called the Hill-Langmuir equation. When a logarithmic scale is used for the x-axis an
S-curve is formed. The steepest part of this curve is usually where half of the receptors is bind and the
concentration at which point this is, is called KA. KA is defined as the concentration of ligand at which
50% is bound to a receptor.
The KA is measured via a so-called scatchard experiment, in which two parallel experiments are done.
One in which a radioactive drug is applied to a certain receptor system. This is shown in figure A,
where the first steep
part is caused by specific
binding of drug, followed
by non-specific binding
of drug. In the second
experiment β-receptors
are block with non-
radiant ligand and
therefore all of the β-
receptors are blocked, and the radiolabelled ligand can only bind
to other kinds of proteins, which represent non-specific binding.
Figure B is a subtraction of the two curves shown in figure A. In
the last graph a linear relationship between the figures is shown.
These graphs shown here are concentration-effect curves. There
is a difference between ligand binding and ligand effect.
Efficacy: the extent to which a drug can active a system
Potency: the concentration at which half of the system is active
Occupation theory: effect (EA) proportional to occupancy (NA)
The efficacy is not always 0 or 1, so the curve is almost never a
linear line. This effect can be calculated with the following formula:
𝜀𝑁𝐴 𝑥𝐴
𝐸𝐴 = 𝜀𝑁𝐴 =
𝑥𝐴 + 𝐾𝐴
When ε = 1, the drug is a full agonist. When 0 < ε < 1, the drug is a partial agonist and when ε = 0 the
drug is an antagonist. pD2 = - log (concentration inducing 50% of maximum effect) = -log (EC50). In the
occupation theory pD2 = -log (KA).
EC50 is the concentration of drug that induces half of the maximum effect of that specific drug. EC50
and pD2 are used only for agonists, since only these drugs induce an effect in the body.
,Occupancy-response relationships
Receptor reserve basically means that
a particular physiological system has
more receptors than it needs to get
fully activated. Only full agonist will
profit from the receptor reserve. For
partial agonists the occupancy and
response relationship stay the same. A
physiological consequence for this is
that an organ expresses very high
levels of a receptor is more sensitive to
a drug than organ which express less receptors.
Antagonists can be classified into
receptor antagonists and
nonreceptor antagonists.
- Competitive antagonist
This is the most common
form of antagonists. A drug
binds to a receptor but fails
to activate it. Agonist can
push the antagonist from
the receptor to activate it.
And this results in the classic curve-shift to the right. In
short, there is a change in EC50, but no change in efficacy.
A parameter derived from this antagonist is the dose ratio:
𝑥′ 𝑥
𝑟𝐴 = 𝑥𝐴 = 𝐾𝐵 + 1. This says something about the degree
𝐴 𝐵
of pharmalogical block from a competitive antagonist. A
Schild plot is made from the results of the dose ratio. In a
Schild plot log (r-1) is plotted versus log (xB). In an abcissal
intercept Schild plot: log (r-1) = 0 and log (xB) = log (KB).
log(𝑟 − 1) = log 𝑥𝐵 − log 𝐾𝐵 and 𝑝𝐴2 = − log 𝐾𝐵
Partial agonist = partial antagonist. When the absence of the full
agonist, the partial agonist provides an effect as usual. When there
is a full agonist present, the partial agonist will eventually make
sure that the efficacy in the end is the same as when there is an absence of full agonist.
- Non-competitive
antagonism
It is dependent on
receptor binding, but it
cannot be competed
away by an agonist. Two reasons are: agonist bind to the same receptor, but in an irreversible
way or the agonist binds to a different receptor and cannot be competed out by an
antagonist. There is loss in maximal effect, but the EC50 stays the same. The non-competitive
‘consumes’ receptors, which means that agonists can bind, but no longer active the receptor.
, When there is receptor reserve and the system is composed to a non-competitive antagonist. There is
no change in effect because less receptors than present are needed for the activation. Therefore, only
when there the amount of non-competitive antagonist is increased a decrease in effect is visible.
When reversible competitive antagonism occurs there is fast dissociation of antagonist. This is also
known as the normal binding model.
[B] + [R] ⇋ [BR]
When irreversible competitive antagonism occurs, there is no dissociation of antagonist:
[B] + [R] → [BR]
This last model is also the case when the antagonist dissociation is very slow. There is non-competitive
antagonist behaviour.
Receptor subtype selectivity of antagonist influences the antagonism because antagonist can be
selective for a particular receptor. In some cases a drug acts more on the β1-receptor and has a lower
effect on the β2-receptor.
Kinetic subtype selectivity of antagonist influences the antagonism because it is a peculiar process,
which is a result of differences in the binding kinetics on different receptor subtypes. The KA-value is
the same, but the dissociation constants are different.
LECTURE 1-2:
Efficacy reflects the relative affinity of the
drug for the resting and activated states
of the receptor.
A receptor which is capable of producing a
biological response in the absence of a
bound ligand is said to display constitutive
activity. This can be blocked by an inverse
agonist; it is the same as antagonism, but
it takes away the baseline of receptor
activity. These antagonists are neutral.
The inverse agonist is nothing more than an antagonist, it decreases the response. 80% of G-protein-
coupled receptor antagonists are inverse agonists. Two-state model oversimplification: multiple
receptor states preferentially stabilized by different ligands.
Multiple-receptor state model basically assumes that are not only
one active and inactive states, but there are multiple active states
possible. Ligands can selects different states that they can bind to
and this explains why some ligand are full and partial agonists.
- Functional (physiological) antagonism
This is a part of nonreceptor antagonism, and it is dependent
on a physiological response. When there are two receptors in
a physiological system which have opposing effects the body
can automatically respond to a specific state in the body. For
example, when there is too much contraction of the airway,
this receptor is blocked, and the relaxation-receptor is
activated by an agonist. It works up to a certain degree;
mostly at higher concentrations it has no effect anymore.
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