Lecture 3: How Drugs Bind to their Targets II Flashcards
What is Agonism?
Binding of drugs to receptors and activation of those receptors
What does the question of whether something is a full or partial agonist relate to?
Efficacy
What is Potency?
The concentration of a drug that will elicit its maximal effect
What is the opposite to an Agonist?
An inverse agonist
What is inverse agonism?
The binding of a drug to a receptor and inhibiting its activation
What is EC50 (Effective Concentration 50)?
The concentration of a drug that yields a 50% maximal effect
What is Emax?
The maximal biological effect observed with a drug
Which part of the graph does EC50 always refer to?
The concentration
What does Antagonism mean?
A substance/drug binds to a receptor and influences its response to an agonist
What is the difference between an Antagonist and an Inverse Agonist?
The application of an antagonist on its own will not have any effect on a receptor whereas an inverse agonist can inhibit the baseline level of a receptor
What is required in order to see the effect of an antagonist?
An agonist must be present
What can happen at increasing large concentrations of the agonist in the presence of a competitive inhibitor?
The agonist can reach the same saturating response as without the competitive antagonist
What changes in a graph with competitive antagonists?
There is a shift in the EC50
What does a competitive antagonist effect?
It affects the potency of the agonist but not the efficacy
What changes in the graph with a non-competitive antagonist?
There is a shift in the efficacy
How does a non-competitive agonist effect a graph?
No matter how much of the agonist is applied, maximum efficacy can never be reached
What does a Non-competitive antagonist effect?
It effect maximal efficacy but does not change the EC50/potency
What remains constant in Non-competitive antagonism?
The EC50/Potency
What remains constant in Competitive Antagonism?
The efficacy or maximal effect
What is the difference between the effects of a competitive antagonist and a non-competitive antagonist?
A competitive antagonist changes the EC50/Potency and a non-competitive antagonist changes the efficacy
What happens with competitive antagonists?
A higher concentration of agonist is required to generate a given response, but agonist efficacy is not changed
What happens with non-competitive antagonists?
They reduce agonist efficacy but have no effect on potency
What is a competitive antagonist?
A compound that occupies the same binding side as an agonist but does not elicit a biological response
What can happen at a high concentrations of an agonist with a competitive antagonist?
The competitive antagonist is displaced an maximal efficacy can be achieved
What is a Schild Plot?
A way to quantify association of competitive antagonist with a receptor
What is calculated in a Schild Plot?
The ratio of the EC50 of an agonist in the presence of antagonist to the EC50 of a control at different concentrations of a competitive antagonists
What does it mean if the concentration of the agonist on a Schild Plot is 2?
The EC50 has been doubled
What does the X-intercept on a Schild Plot represent?
The Potency of an antagonist
What means a high potency of an antagonist?
A small concentration needed to double the EC50
What do Competitive Antagonists do?
They shift the EC50 but do not change the overall maximal effect
What is an example of a Competitive Antagonist?
Naloxone which is a competitive antagonist for opioids
What can partial agonists appear to act as?
Antagonists
How can partial agonists act as antagonists?
The partial agonist can compete for the binding spot with the full agonist
What happens to Emax when a partial agonist acts as an antagonist?
It decreases the maximal response because the partial agonist can only elicit a fractional response
What is Agonism always related to?
Efficacy
Why do partial agonist appear to act as antagonists in the presence of full agonists?
Because when the partial agonist competes for the binding site against the full agonist, when it wins the battle, the partial agonist only shows the a fraction of the maximal effect
What occurs in Irreversible Competitive Antagonism?
The antagonist binds irreversibly to the drug binding site and cannot be displaced by increasing agonist concentration
How is Emax affected by Irreversible Competitive Antagonism?
The peak response decreases in response to an increase in concentration of irreversible a competitive antagonist even with an increased concentration of the agonist
What does a Non-competitive Antagonist do in terms of efficacy and potency?
It will reduce agonist efficacy but not potency
What is the Orthosteric binding site?
The site where the agonist binds
What are Allosteric sites?
Distinct sites on the receptor where modulators can bind
Which sites do non-competitive inhibitors bind?
They bind to allosteric sites
What happens in the presence of a non-competitive inhibitor when there is increasing agonist concentration?
No matter how much agonist concentration is increased Emax cannot be achieved
What remains constant with a non-competitive antagonist?
Non-competitive antagonists do not shift EC50
What does binding of an non-competitive antagonist do physiologically?
It prevents the activation of the agonist bound receptor, or it might alter the properties of the agonist binding site, leading to a combination of effects on potency and efficacy
What are Allosteric Potentiators?
Drugs that when bound to the allosteric site they enhance to receptor response to agonist binding
How do Allosteric Potentiators affect potency and efficacy?
They increase the potency and sometimes efficacy of a drug
How are GABA receptors affected by chronic alcohol and withdrawal?
Normal GABA receptors allow chlorine into the cell causing hyperpolarization but with alcohol they have less GABA receptors and cells are hyperexcitable
Why do people going through alcohol withdrawal often have seizures?
Because the GABA receptors that stop hyperexcitability are removed
What do Benzodiazepines do?
They are positive allosteric modulators and potentiate signals from GABA receptors causing the EC50 to decrease
What is binding quantified with?
The dissociation constant
What is the dissociation constant (kd)?
The concentration of a drug where 50% of the receptors are bound
What is Bmax?
The maximal fraction of receptors that can be bound
What is Kd used to refer to?
The potency of direct binding of a drug to a receptor
Why is there a mismatch between the binding of a drug to a receptor and the effect that is observed?
There are more receptors present than are required for activation of a full biological effect
What does the Receptor Reserve depict?
The difference between binding and effect
What occurs in a receptor reserve graph?
First there is a shift in the EC50 then a loss of efficacy due to the increased binding of a irreversible competitive antagonist
What steps happen in receptor reserve graph to look the way it does?
As there are increasing amount of irreversible competitive inhibitor but there is an excess of receptors needed to produce maximal effects the EC50 initially shifts down because increasing concentration of the agonist needed to fill all the available receptors. Eventually as all the receptors become filled, the efficacy of the agonist decreases because the competitive antagonist has taken up all the receptor spots.
What does it look like in the two sections of a receptor reserve graph?
It first appears to look like a competitive antagonist then it appears to look like a non-competitive antagonist
