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Summary Receptor Pharmacology (WBFA036-05)
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Summary of all lectures of the course Receptor Pharmacology
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Receptor Pharmacology Fien RozendaalLecture 1 Agonism, Antagonism, receptor statistics
Pharmacology: interaction of chemical substances with the living organism
Non-specific: biological effect at relatively high drug concentration these are drugs that
not directly interact with a receptor or an enzyme
Specific: Biological effect at relatively low drug concentrations.
Chemical and biological specificity
Act directly on the target
Individual classes of drugs bind to discrete receptors while individual receptors recognize
only discrete classes of drugs.
High specificity by high affinity
No drugs are completely specific in their action
Side effects may occur by relatively high drug concentrations, due to binding to other targets
(receptors) with lower affinity
- On target side effects Cause of binding to the same receptor. Binding on the
same receptor as were the drug is supposed to work on but the receptor has more
than one physiological function and the side effect is the result of these different
functions. Very difficult to prevent.
- Off target side effect Binding to a different receptor (target)
Agonist: Receptor occupation leads to biological response
Antagonist: Receptor occupation doesn’t not lead to response & and prevents the effect of
an agonist, mostly by preventing from binding.
Agonist versus Antagonist
Agonist: acetylcholine
Antagonist: atropine
Acetylcholine is an agonist which causes a decrease in
blood pressure and the antagonist of this is atropine.
Ka = Binding constant/Affinity constant
is defined as the concentration of ligand at which 50%
of the receptor is bound.
- Lower number means higher affinity / more potent
B/xA = (Bmax-B)/KA describes the amount of drug that is
specifically bound.
The extend to which a drug can activate the system efficacy
Potency describes the concentration at which half of the system
is activated.
Drug A is more potent than drug B because it activates the system
already at lower concentrations than drug B does. But these drugs
has the same efficacy.
Potency is the same as EC50, not the same as Ka: 50% binding
does not mean 50% effect. EC50 always smaller than Ka.
1
,PD2 higher, potency is high
EC50 higher, potency is not high
The intrinsic efficacy: describes how much of a receptor is activated in a binding. If the
intrinsic activity is 1, all of the receptor is activated full agonist.
When none of the receptor is activated than the intrinsic activity is 0 antagonist
When the intrinsic activity is between 0 and 1 it is a partial agonist
A partial agonist is a ligand that can bind to the receptor however the efficacy in
transducing and effect is not the same as for a full agonist
PD2 = -log concentration inducing 50% of maximum effect
(-log EC50; occupation theory = -log KA)
EC50 and PD2 are terms which are only used for agonists.
Theoretical occupancy and
response curves for full and
partial agonists
Brown curve: relation between
the agonist concentration and
the binding curve between
both drugs.
A partial agonist does not
benefit from the receptor
reserve. Because a partial
agonist can not activate the
whole system.
Reversible competitive antagonism
Most common form of antagonism.
More antagonist shifts the effect (%) to the right
2
, o Agonist will outcompete the antagonist at a higher concentration
Characteristics:
o The maximum effect does not change
o Rightward shift of concentration curve
You need more agonist in the system however when the dose is high enough, you can still
reach max effect. The antagonist is in equilibrium with the receptor bound form. The
association and dissociation are both relatively quick.
Partial agonism/antagonism
When there is a change in the amount of antagonist than there will be a change in potency
but no change in efficacy
Partial agonist = Partial antagonist
o The effect of a full agonist combined with a partial agonist will have the same
effect as the partial agonist
Useful for cardiac arrhythmia treatment: Modifying heartbeat
The dose ration describes how much more agonist you need to compensate for the
antagonist.
Schild plot
- Intercept: Binding constant of antagonist: Kb
- Calculate pA2= -log Ka
- pA2: Intercept of the Schild Plot that describes the potency of the antagonist
Concentration at which the antagonist will prevent 50% of agonist binding
- If you add ten times more antagonist than you also have to add ten times more
agonist to compensate if you want to activate the receptor.
Partial agonist B combined with various concentration of an agonist A, acting on the same
receptor system:
- When there is added more full agonist system becomes more and more activated.
- In the absence of the full agonist, the partial agonist will just activate the system a bit
it activates the system for 40%
Not al B-agonists used for the treatment of asthma and COPD are full agonists.
Isoprenaline and Formoterol are full agonists
Salbutamol and Salmeterol are partial agonists
Sometimes it is better to use a partial agonist to block some other kinds of agonists. Partial
antagonist can block other agonists and this can be good for the
system.
Non-competitive antagonism
Depends on receptor binding however it can not be competed away by
the agonist. Reasons:
- agonist binds to the same side of the receptor but in an irreversible
way
- agonist binds by a different side of the receptor that can not be
competed out by the antagonist.
3
, Characteristics:
1. Lowered efficacy
2. No relative change in EC50
- opposite of competitive antagonism
- Drugs bind at a different spot, but the agonist will take out the receptor the antagonist binds
with, resulting in lowered max effect
- Receptor reserve can cause a shift to the right (in the Effect%-concentration curve)
depending on how large the reserve is.
Exam Guaranteed question:
2 binding constants are given, for which receptor is the drug selective?
The drug is selective for the receptor with a smaller binding constant.
The drug binds easier to the receptor with the smaller Ka because less
concentration is needed for a similar effect.
Receptor reserve = there are more receptors available then you need. There is already a
maximum effect but still too much receptors
The non-competitive antagonist B first induces a shift to the right; depression of the
maximum occurs only after the receptor reserve of the full agonist A has been exhausted.
A full agonist benefits from receptor reserve, because you need less receptor bound for
activation of the system. When you take the receptor reserve away the graph will shift to the
right.
Irreversible competitive antagonism
- Antagonist wins over agonist’
- The antagonist can no longer dissociated receptor disabled
- Drop in maximum effect
Non-competitive-like antagonism
Tiotropium: Slowly dissociating, receptor available after a long time
- Rightward shift in the Effect% - Concentration graph
- Drop in maximum effect
Kinetic subtype selectivity of antagonists
Tiotropium binds relative the same for M1, M2, M3 receptors. The dissociation half life is
more different. If you apply Tiotropium to the lung than you will see that the M3 will stay
longer in the lung than the M2 receptor.
The M3 is bound really tightly so it sticks around
longer.
Aclidinium and Glycopyrronium have the same
behaviour.
The top graph depicts the situation for the M3
receptor and the lower graph depicts the situation
for M2.
M3 has a much longer half time than the M2
receptor. After a couple hours we still have a
considerable amount of M3 receptors but all the M2
4
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