Lecture 3- How drugs bind to their targets Flashcards
Where do agonists bind?
Orthosteric binding site
Where do competitive inhibitors bind?
Also the orthosteric site
Where do allosteric modulators bind?
Allosteric sites
What is the difference between agonism and antagonism?
- Agonism refers a substance/drug binding to a receptor and influences its activty
- Antagonism refers to a substance/drug binding to a receptor an influencing its response to an agonist.
Agonists bind to a receptor and usually ____ the activity of a receptor. Inverse agonist ____ the activity of the receptor
increase;reduce
What are the 2 types of antagonists?
competitive and non-competitive
A ____ antagonist requires a higher concnetration of agonist to generate a given response, but agonist efficacy is not changed. They will shift the apparent potency to the agonist and EC50 will be ____ when it is present.
competitive; higher
A ____ antagonist reduces agonist efficacy but no effect on its potency. It will have no shift in its apparent potency and the EC50 will be ____ but you will have a reduction in the efficacy and this is an insurmountable reduction
non competitive; same
A competitive antagonist occupies the ____ binding site as the agonist but does not eflicit a biological response.
same
At ____ enough agonist concentrations, the antagonist is displaced and maximal ____ can be achieved; sometimes called a ____ antagonist
- high
- efficay
- surmountable
The ____ inhibitor you have, the ____ agonist you need.
more;more
Since a competitive antagonist ____ generate a biological effect on its own, it can be difficult to measure how antagonists interact with receptor.
does not
What is illustrated based on the dose ratio or the concentration?
Schild plot
What is a dose ratio
indicates the fold increase of the agonist needed to achieve the same response at a given concentration of antagonist
____ concentrations of antagonist require a ____ concentration of agonist to generate a maximal response
larger; larger
Competitive antagonists exhibit a ____ schild plot
linear
The x-intercept is sometimes refered to as the pA2 or pKi and reflects the ____ of the antagonist
potency
The more strongly binding the antagonist is to the receptor, the ____ the concentration will be, the more ____ shifted it will be on the X-axis.
smaller; left
The more weakly binding the antagonist is to the receptor, the more shifted it is to the ____ on the curve and therefore, the ____ antagonist is needed to generate a big shift in the EC50 of the agonist
right;more
Competitive antagonists shift the apparent potency of the agonist but ____ chance the efficacy.
do not
As you add more competitive antagonist, you shift the cocnentration response curve more and more to the ____. The more agonist you have, the ____ antagonist you need to inhibit. The more antagonist you have, the ____ agonist you need to relieve the inhibiton.
right; more; more
True or False: An antagonist that leads to a small shift in the EC50 is weakly potent, it binds less strongly to the agonist
True
Provide an important example of a competitive antagonist (think opioid overdose)
Naloxone (‘Narcan’) is a competitive non-specific opioid receptor antagonist used as an antidote for opioid overdoses
How can partial agonists act as antagonists?
By competing for binding with the full agonist - lead to decreased overall response
____ ____antagonism is when an antagonist binds irreversibly to the orthosteric site by forming a covalent bond and can’t be displaced resulting in ____ efficacy.
Also known as non-competitive antagonism
Irreversible competitive; reduced
What is a non-competitive antagonist and where do the non-competitive antagonists bind?
- A non-competitive antagonist will reduce agonist efficacy but NOT its potency (no shift in EC50)
- No matter how much agonist is administered, a full effect is not observed.
- It binds to the Allosteric site
Binding of the non-competitive antagonist might prevent ____ of the agonist bound receptor
activation
- What are positive allosteric modulators (PAMS)?
- Are smaller concentrations or larger concentrations prefered to elicit a good response in presence of a PAM?
- They are drugs that interact with the allosteric site and increase to ability of the agonists to activate the receptor
- Smaller concentrations of the agonists are required to elicit a good response in the presence of a PAM
Gaba receptors are ____ receptors. When they are open, they have a ____ effect on our brain. They prevent neurons from firing in our brain. They also prevent seizures, anxiety or hyperstimulation if taken at a ____ to ____ dose. When an individual abuses alcohol chronically and then stop, they have withdrawal symptoms such as hallucinations, extreme anxiety, seizures and shaking tremors. They happen because chronic use of alcohol cause a ____ of gaba receptor levels in the brain
- inhibitory
- suppressive
- low-medium
- reduction
What is another example of a positive modulator of Gaba receptors?
- Benzodiazepines; it has an EC50 and the more GABA you add, the higher the activity of the channels.
- Benzodiazepines act to shift the concentration response to smaller concnetrations of the agonist.
Waht method is used to evaluate pharmalogical properties of an antagonist?
Schild plot
What does Kd represent in the equation below?
- It is the dissociation constant which is used to refer to the potency of direct binding of a drug to a receptor
- it gives you 50% of the full occcupancy of the receptors bound by the ligand
Why can there be a mismacth between binding and effect?
(use GCPR as an example)
- there are more receptors present than are required for activation of a full biological effect.
- i.e., activation of a single g-protein can lead to many cAMP molecules and activation of many effector protein. Due to the amplifying effects, there is not a direct relationship between agonist binding and biological effect.
