Receptor Pharmacology 2018/2019
General pharmacological principles
Pharmacology are interactions of chemical substances (drugs) with the living organism.
Pharmacokinetics is the science that studies what the body does with the pharmacon.
Pharmacodynamics is about the effect of the drug.
Drug action
Drug is a chemical applied to a physiological system that affects its function in a specific way. A
nonspecific drug is when there is a biological effect at relatively high drug concentrations. A specific
drug is when the biological effect is at relatively low drug concentrations and when there is chemical
and biological specificity. Most drugs act on target proteins with high affinity to the drug. Target
proteins are receptors, ion channels, enzymes and carriers. Receptors are target molecules whose
function is to recognize and respond to specific endogenous chemical signals, such as hormones,
neurotransmitters and inflammatory mediators. Individual classes of drugs bind to discrete receptors,
while individual receptors recognize only discrete classes of drugs. High specificity by high affinity.
However, no drugs 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.
Agonists and antagonists
An Agonist for example acetylcholine, is a receptor occupation that leads to a biological response.
The receptor becomes active. An antagonist is for example atropine, is a receptor occupation that
doesn’t lead to a response and it prevents the effect of an agonist, mostly by preventing it from
binding. Activation is governed by efficacy and occupation is governed by affinity.
The hill-langmuir equation describes the relationship between the concentration and the affinity of
the agonist and the receptor occupancy. With the equation you can determine the occupation of the
receptor. Ligand binding depends on the concentration of ligand and the affinity of the ligand to the
receptor. The Ka (bindings constant) is the concentration of agonist when half of the ligand is bound
and half of the receptors are occupied. The Ka is the affinity of the agonist. The Ka should be as low
as possible because the concentration can be lower to activate the receptor and therefore there are
less side effects. The lower the Ka the higher the affinity.
Scatchard analyse, a radioactive ligand is added in increasing concentrations. The binding constant
and the total number of receptors can be determined. The non-specific binding can be determined
by adding a not labeled competitive antagonist. Then you can subtract the non-specific binding from
the total binding.
,Concentration-effect curves
Efficacy is the maximal biological effect in other words Emax. It is the maximum respons. Potency, is
the concentration that is needed to bind. Potency and efficacy have to do with effect. Binding and
scatchard have to do with binding.
The intrinsic efficacy can differ from zero to one. When the intrinsic efficacy is one we speak of a full
agonist. When the intrinsic efficacy is somewhere between zero and one it is called a partial agonist.
The partial agonist dominates the system. It competes with the full agonist. The partial agonist is
hindered by the full agonist. The partial agonist is also a partial antagonist. By an intrinsic efficacy of
zero it is called an antagonist. A full agonist induces the maximal activation of the receptor system. A
partial agonist does not achieve the maximal activation of the receptor system. EC50, the drug
concentration when there is an effect of 50 %. The EC50 determines the potency. The lower the
binding constant the higher the potency. So, a drug with a high potency has a low EC50.
Compound A binds to the receptor with a Ka of 1 x 10^-6. Compound B with a
Ka of 1 x 10^-7. Which is more potent? It is compound B.
pD2 is the – log of EC50. pD2 is a term which describes affinity. The higher the pD2, the higher the
affinity.
By a receptor are levels of activations. There are different active states of receptors. Therefore, it can
be partially activated.
The relationship between binding and function are distorted when there is receptor reserve. By
receptor reserve is the EC50 always lower than your binding constant. The EC50 is equal at the
binding constant when there is no receptor reserve. Receptor reserve shifts the curve to the left. It
makes your agonist more potent. In case of a partial agonist it makes your agonist more efficacy.
Receptor reserve has to do with efficacy. When there is no efficacy it doesn’t matter how much
receptors there are.
The ability of a drug to bind to a binding pocket depends on the structure. The bulkier the structure
the less binding. When the efficacy is lost the agonist becomes an antagonist.
Antagonist classification
,There are two kinds of receptor antagonists those who bind at the active site and those who bind
somewhere else (allosteric binding). By allosteric binding binds the antagonist not at the same place
as the agonist.
Competitive reversible antagonism, the antagonist inhibits the
binding and the effect of the agonist by competing for the same
receptor binding spot. The maximum effect of the agonist can be
achieved by increasing the concentration of the agonist. The curve is
equal but shifts to the right. The more agonist you add the more the
change in shift to the right.
Competitive irreversible antagonism, the antagonist binds
irreversible on the place where the agonist normally bound. The
maximum effect van no longer be reached.
Dosis ratio is the EC50 of the agonist in the presence of the
antagonist / the EC50 of the agonist in the absence of the
antagonist. It describes the change in EC50.
A schild plot is a way to calculate the pA2 and the dosis ratio.
Non-competitive antagonism or allosteric antagonism, it disables
the receptor. The agonist can no longer activated. ion channels do
non-competitive antagonism. The non-competitive cannot be
competed out by the agonist because it has no affinity for that site.
By competitive antagonism there is no difference in potency. By non-competitive there is a difference
in potency. It depends on how much of the receptors are bind to the non-competitive antagonist.
First a chance in potency and then in efficacy. The lowest binding constant is the most selective
antagonist.
Two state model
Receptors can occur in an active or an inactive state. An agonist prefers to bind at an active receptor.
So, the equilibrium shifts to the active site. Receptors can be active by itself. It is called constitutive
activity. Efficacy reflects the relative affinity of the drug for the resting and activated states of the
receptor. An inverse agonist stabilized the inactive state of the receptor. The activity in the system
gets lower. A neutral agonist doesn’t give preference to an inactive or an active receptor. They cause
competed antagonism
, Non-receptor antagonists
Functional (physiological) antagonism it’s the inhibition of the effect of the agonist by activating a
receptor who has the opposite biological response.
Chemical antagonism
It doesn’t require a chemical system (cell). Examples are neutralizing antibodies, antacids, chelators.
It is a direct reaction; the drug reacts directly on the mechanisms. Often, they are non-receptor
antagonists and they often block cytokines. There is a mixture of two substances.
Pharmacokinetic antagonism
A drug accelerates the degradation of another drug and makes it thereby less effective. For example,
by an increased rate of metabolic degradation and decreased gastrointestinal absorption (increased
gastric motility).
Receptor regulation
Desensitization, tachyphylaxis and tolerance are the same thing, it is the loss of response to a drug.
- There is a change in receptors; loss of receptors
- Exhaustion of mediators
- Enhanced drug metabolism
- Compensatory physiological mechanisms
- Extrusion of drugs from cells
Receptor desensitization
Receptor desensitization takes places with a damaged GPCR. The damage is caused through long-
term stimulation. The receptors become less sensitive to the agonist. The intracellular domains of the
receptor are phosphorylated by GRK and PKC/PKA. Phosphorylating makes it impossible to bind.
Uncoupling of the receptor; the receptor is still there but binding is not possible. A rapid loss of
response follows. There are two phases of desensitization; a quick loss of the receptor function, from
this point the loss can recover fast, it is reversible. In the second phase there is a loss of response.
The phosphorylated receptors are recognized by arrestin. It triggers an endocytose response.
Arrestin removes the receptors of the membrane. It takes longer to recover the desensitization.
Over expression of the drug causes desensitization of the receptors, it can be helpful as well.
General pharmacological principles
Pharmacology are interactions of chemical substances (drugs) with the living organism.
Pharmacokinetics is the science that studies what the body does with the pharmacon.
Pharmacodynamics is about the effect of the drug.
Drug action
Drug is a chemical applied to a physiological system that affects its function in a specific way. A
nonspecific drug is when there is a biological effect at relatively high drug concentrations. A specific
drug is when the biological effect is at relatively low drug concentrations and when there is chemical
and biological specificity. Most drugs act on target proteins with high affinity to the drug. Target
proteins are receptors, ion channels, enzymes and carriers. Receptors are target molecules whose
function is to recognize and respond to specific endogenous chemical signals, such as hormones,
neurotransmitters and inflammatory mediators. Individual classes of drugs bind to discrete receptors,
while individual receptors recognize only discrete classes of drugs. High specificity by high affinity.
However, no drugs 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.
Agonists and antagonists
An Agonist for example acetylcholine, is a receptor occupation that leads to a biological response.
The receptor becomes active. An antagonist is for example atropine, is a receptor occupation that
doesn’t lead to a response and it prevents the effect of an agonist, mostly by preventing it from
binding. Activation is governed by efficacy and occupation is governed by affinity.
The hill-langmuir equation describes the relationship between the concentration and the affinity of
the agonist and the receptor occupancy. With the equation you can determine the occupation of the
receptor. Ligand binding depends on the concentration of ligand and the affinity of the ligand to the
receptor. The Ka (bindings constant) is the concentration of agonist when half of the ligand is bound
and half of the receptors are occupied. The Ka is the affinity of the agonist. The Ka should be as low
as possible because the concentration can be lower to activate the receptor and therefore there are
less side effects. The lower the Ka the higher the affinity.
Scatchard analyse, a radioactive ligand is added in increasing concentrations. The binding constant
and the total number of receptors can be determined. The non-specific binding can be determined
by adding a not labeled competitive antagonist. Then you can subtract the non-specific binding from
the total binding.
,Concentration-effect curves
Efficacy is the maximal biological effect in other words Emax. It is the maximum respons. Potency, is
the concentration that is needed to bind. Potency and efficacy have to do with effect. Binding and
scatchard have to do with binding.
The intrinsic efficacy can differ from zero to one. When the intrinsic efficacy is one we speak of a full
agonist. When the intrinsic efficacy is somewhere between zero and one it is called a partial agonist.
The partial agonist dominates the system. It competes with the full agonist. The partial agonist is
hindered by the full agonist. The partial agonist is also a partial antagonist. By an intrinsic efficacy of
zero it is called an antagonist. A full agonist induces the maximal activation of the receptor system. A
partial agonist does not achieve the maximal activation of the receptor system. EC50, the drug
concentration when there is an effect of 50 %. The EC50 determines the potency. The lower the
binding constant the higher the potency. So, a drug with a high potency has a low EC50.
Compound A binds to the receptor with a Ka of 1 x 10^-6. Compound B with a
Ka of 1 x 10^-7. Which is more potent? It is compound B.
pD2 is the – log of EC50. pD2 is a term which describes affinity. The higher the pD2, the higher the
affinity.
By a receptor are levels of activations. There are different active states of receptors. Therefore, it can
be partially activated.
The relationship between binding and function are distorted when there is receptor reserve. By
receptor reserve is the EC50 always lower than your binding constant. The EC50 is equal at the
binding constant when there is no receptor reserve. Receptor reserve shifts the curve to the left. It
makes your agonist more potent. In case of a partial agonist it makes your agonist more efficacy.
Receptor reserve has to do with efficacy. When there is no efficacy it doesn’t matter how much
receptors there are.
The ability of a drug to bind to a binding pocket depends on the structure. The bulkier the structure
the less binding. When the efficacy is lost the agonist becomes an antagonist.
Antagonist classification
,There are two kinds of receptor antagonists those who bind at the active site and those who bind
somewhere else (allosteric binding). By allosteric binding binds the antagonist not at the same place
as the agonist.
Competitive reversible antagonism, the antagonist inhibits the
binding and the effect of the agonist by competing for the same
receptor binding spot. The maximum effect of the agonist can be
achieved by increasing the concentration of the agonist. The curve is
equal but shifts to the right. The more agonist you add the more the
change in shift to the right.
Competitive irreversible antagonism, the antagonist binds
irreversible on the place where the agonist normally bound. The
maximum effect van no longer be reached.
Dosis ratio is the EC50 of the agonist in the presence of the
antagonist / the EC50 of the agonist in the absence of the
antagonist. It describes the change in EC50.
A schild plot is a way to calculate the pA2 and the dosis ratio.
Non-competitive antagonism or allosteric antagonism, it disables
the receptor. The agonist can no longer activated. ion channels do
non-competitive antagonism. The non-competitive cannot be
competed out by the agonist because it has no affinity for that site.
By competitive antagonism there is no difference in potency. By non-competitive there is a difference
in potency. It depends on how much of the receptors are bind to the non-competitive antagonist.
First a chance in potency and then in efficacy. The lowest binding constant is the most selective
antagonist.
Two state model
Receptors can occur in an active or an inactive state. An agonist prefers to bind at an active receptor.
So, the equilibrium shifts to the active site. Receptors can be active by itself. It is called constitutive
activity. Efficacy reflects the relative affinity of the drug for the resting and activated states of the
receptor. An inverse agonist stabilized the inactive state of the receptor. The activity in the system
gets lower. A neutral agonist doesn’t give preference to an inactive or an active receptor. They cause
competed antagonism
, Non-receptor antagonists
Functional (physiological) antagonism it’s the inhibition of the effect of the agonist by activating a
receptor who has the opposite biological response.
Chemical antagonism
It doesn’t require a chemical system (cell). Examples are neutralizing antibodies, antacids, chelators.
It is a direct reaction; the drug reacts directly on the mechanisms. Often, they are non-receptor
antagonists and they often block cytokines. There is a mixture of two substances.
Pharmacokinetic antagonism
A drug accelerates the degradation of another drug and makes it thereby less effective. For example,
by an increased rate of metabolic degradation and decreased gastrointestinal absorption (increased
gastric motility).
Receptor regulation
Desensitization, tachyphylaxis and tolerance are the same thing, it is the loss of response to a drug.
- There is a change in receptors; loss of receptors
- Exhaustion of mediators
- Enhanced drug metabolism
- Compensatory physiological mechanisms
- Extrusion of drugs from cells
Receptor desensitization
Receptor desensitization takes places with a damaged GPCR. The damage is caused through long-
term stimulation. The receptors become less sensitive to the agonist. The intracellular domains of the
receptor are phosphorylated by GRK and PKC/PKA. Phosphorylating makes it impossible to bind.
Uncoupling of the receptor; the receptor is still there but binding is not possible. A rapid loss of
response follows. There are two phases of desensitization; a quick loss of the receptor function, from
this point the loss can recover fast, it is reversible. In the second phase there is a loss of response.
The phosphorylated receptors are recognized by arrestin. It triggers an endocytose response.
Arrestin removes the receptors of the membrane. It takes longer to recover the desensitization.
Over expression of the drug causes desensitization of the receptors, it can be helpful as well.
