Lecture 3: How Drugs Bind to Their Targets (Part 2)

Question 1

What does agonism mean?

Answer 1

means that a substance/drug binds to a receptor and influences its activity

this is usually depicted as a “concentration-response” curve

Question 2

What does antagonism mean?

Answer 2

means that a substance/drug binds to a receptor and influences its response to an agonist

Question 3

What are competitive antagonists?

Answer 3

a higher concentration of agonist is required to generate a given response, but agonist efficacy is not changed

a competitive antagonist is described as a compound that occupies the same binding site as the agonist, but does not elicit a biological response

at high enough agonist concentrations, the antagonist is displaced, and maximal efficacy can be achieved (sometimes called a “surmountable antagonist”)

since a competitive antagonist does not generate a biological effect on its own, it can be difficult to measure how antagonists interact with receptor

Question 4

What are non-competitive antagonists?

Answer 4

reduce agonist efficacy but no effect on potency

Question 5

What is a Schild plot?

Answer 5

one approach is to generate a “Schild plot” based on a parameter called the “dose ratio” or “concentration ratio”

Question 6

What is the dose ratio?

Answer 6

the “dose ratio” is the ratio of agonist EC50 in the presence vs. absence of antagonist

this is done for multiple concentrations of antagonist

Question 7

What is the formula for dose ratio?

Answer 7

dose ratio = EC50 (in the presence of antagonist)/EC50 (control

Question 8

How does a Schild plot reflect the potency of the antagonist?

Answer 8

larger concentrations of antagonist require a larger concentration of agonist to generate the maximal response

competitive antagonists exhibit a linear Schild plot

the x-intercept is sometimes called the pA2, or pKi, and reflects the potency of the antagonist

Question 9

What is irreversible competitive antagonism?

Answer 9

another way that competition between agonists and antagonists can reduce the apparent efficacy is if the antagonist binds irreversibly to the drug binding site (and cannot be displaced by increasing agonist concentration)

this is sometimes referred to as non-competitive antagonism, but a more accurate term is irreversible competitive antagonism

Question 10

What are allosteric antagonists?

Answer 10

non-competitive inhibition is due to antagonist binding at a different site, distinct from the agonist (usually referred to as an “allosteric site”)

binding of the antagonist might prevent activation of the agonist bound receptor (pure non-competitive antagonism)

alternatively, the binding of the antagonist might alter the properties of the agonist binding site, leading to a combination of effects on potency and efficacy

Question 11

What is allosteric potentiation?

Answer 11

some commonly used drugs can have an allosteric effect (away from the agonist binding site) that acts to potentiate/enhance the effects of an agonist (increased efficacy or potency, or both)

Question 11

What are positive allosteric modulators?

Answer 11

alcohol dependence involves re-modeling in neurons, including down-regulation of GABA a receptor

symptoms of alcohol withdrawal can be mild to severe: anxiety, tremors, delirium, seizures

actions of Benzodiazepines potentiate signals from GABA a receptor that are present - this helps to alleviate some symptoms

potentiate GABA-induced currents (increased frequency of channel opening)

very selective for GABA receptors

high clinical relevance

Question 12

What is the difference between drug binding versus effect?

Answer 12

it is important to recognize that there is not always a direct relationship between the fraction of receptors that are bound to a drug, and the biological response

even though they can be described by similar equations, drug effect and drug binding do not necessarily have the same concentration dependence

different terminology is often used to distinguish these measurements

EC50 is used to describe the potency of a drug in the context of measurement of an effect

Kd (dissociation constant) is used to refer to the potency of direct binding of a drug to a receptor (measured by something like a radioligand binding assay)

Question 13

Why can there be a mismatch between binding and effect?

Answer 13

a common explanation is that there are more receptors present than are required for activation of a full biological effect

for example: activation of a single GPCR can lead to generation of many cAMP molecules and activation of many effector proteins; because of these amplifying effects, there is not a direct relationship between agonist binding and biological effect

Question 14

What is receptor reserve?

Answer 14

the difference between binding and effect is illustrated by a phenomenon called receptor reserve

also true for non-competitive antagonist

when this is observed, application of small concentrations of an irreversible antagonist binds to a fraction of receptors, and prevents them from being activated - but the full biological effect is observed

all the receptors are involved in generating the biological effect, so the Kd and EC50 are very similar