Receptor theory Flashcards
What is KD?
Dissociation constant - measure if affinity. Concentration of ligand the binds to 50% of the receptors. The smaller the KD = the higher the affinity
Relationship between KD and affinity?
Smaller KD = higher affinity
What is the Ki value?
Concentration of competing ligand required to displace 50% of the specific binding of radioligand
What affects Ki values?
the assay conditions and dependent on the concentration of ligand
relationship between affinity and Ki?
Highest affinity has the lowest Ki value
why are higher affinities desired?
If there is a better affinity for the receptor - it means you need less of the drug for an effect - less chance of S/E and less damage to the organs
What is an agonist?
bind to receptors and Activate them to initiate a response
Define EC50
Concentration of drug that causes half the maximal effect produced by the drug (agonist) - measure of potency
Define antagonist
Drug that binds to a receptor but does not activate it - zero efficacy. Blocks the action of the agonis & competes for receptor binding.
Define IC50
Concentration of antagonist to inhibit 50% of the agonist response. Sometimes it can be an over or underestimation depending on the concentration of the agonist present.
what information does the IC50 NOT provide?
NO info on the mechanism e.g. if it is competitive, reversible, non competitive etc
Dose ratio equation?
EC50 + [antagonist] / EC50 of control
What happens to the agonist in presence of an antagonist ?
We need more agonist (higher conc) to produce the same response as it would be without the antagonist present - log curve shifts to the right. Dose ratio >1
This is called competitive surmountable antagonism
What happens when we add more competitive surmountable antagonist?
Reduces the amount of receptor-agonist complex and thus less effect.
what does surmountable mean?
increase in antagonist pushes equilibrium to get less agonist effect
In the presence of what type of antagonist will you eventually get the agonist maximal response?
Competitive surmountable antagonist
Define dose ratio
The fold increase in agonist concentration that is needed to evoke a given response (normally EC50) in the presence of an antagonist
What does antagonist do to the dose ratio?
Increases it
What does a dose ratio of 2 mean?
Twice as much agonist is required to produce the same response
What does a straight line = 1 on schild plot show?
we have a competitive antagonist, it also gives us the log KB
Define KB
The concentration of antagonist that binds to 50% of receptors - a measure of affinity
Relationship between KB and affinity, and PKB and affinity (antagonist)
The lower theKB = higher the affinity of antagonist.
PKB is the negative of KB so the higher the PKB = higher the affinity.
PKB = -logKB
how do you calculate PKB?
-logKB
What is PKB also referred to as?
The PA2 value - measure of affinity & potency.
The concentration of antagonist required to produce an agonist dose ratio of 2.
Give an example of a competitive antagonist
Candesartan - anti-hypertensive/heart failure - an antagonist of angiotensin II = reduce peripheral resistance - vasodilation
When is the PKB/PA2 value only a valid measure of affinity?
ONLY if the antagonist is competitive and reversible (slope = 1 schild)
2 types of insurmountable antagonism
Irreversible
Allosteric
Insurmountable antagonism Definition
In the presence of antagonist, no matter how much agonist you add, you will NEVER elicit the maximum response
what is non-competitive allosteric antagonism?
Bind to different site - form another complex to prevent receptor from causing an effect. Have free agonists and thus less complex being formed and less effect.
Compare competitive and non-competitive antagonism
Competitive competes for receptor sites, more sites occupied and less effect.
Whereas non - just binds to a different site and changes conformation to reduce the agonist complex
2 types of irreversible antagonism
competitive - compete for same binding site.
Non competitive - lock receptor into irreversible state
are irreversible antagonists used clinically?
Not really, some antibody based biologics that lock receptor but no small molecule drugs.
Most drugs can target ENZYMES as irreversible inhibitors (suicide inhibitors ) e.g aspirin but not receptors.
3 things that bioassays tell us about antagonists?
Type of antagonism e.g competitive/surmountable, non competitive, insurmountable? if it is insurmountable then implications e.g could overdose with anticoagulants
Dissociation constant= affinity for competitive antagonists - KB
drug effects
Define efficacy
The ability of a drug to activate a receptor and cause a. response - response is dependent on amount of receptors occupied.
What is a partial agonist?
Some agonists cannot evoke the maximal response that a tissue can produce = lower Emax
Full agonist = 1
Partial agonist = <1
what is potency based on?
EC50 value
Why doesn’t receptor occupancy theory explain partial agonists?
A full agonist causes a near maximum response at 50% occupancy of receptors (e. g phenylephrine at a-1 adrenoceptors). However, partial agonists can never cause max response even at 100% occupancy. The theory does not explain partial agonists as receptors occupied at the same extent. This - the response can’t be directly proportional to stimulus
How does intrinsic activity explain partial agonists? - modified occupancy theory
Response is governed by occupancy and efficacy.
Intrinsic efficacy factor (beta) determines drug type e.g
B = 1 - full agonist
B = <1 partial agonist
B = 0 antagonist
Advantages of partial agonists as drugs
- submaximal tissue response - does not stimulate fully the system
- Less desensitisation
- can also act as competitive inhibitors of full agonists
Drug that is a partial agonist
Buprenorphine - For opioid dependence and pain relief (Temgesic)
Partial agonist at opioid receptors - don’t get full response desensitisation
what is the theory of receptor reserve?
Maximal response can be obtained with submaximal occupation - irreversible agonism - the agonist can still produce max response even if occupancy is only 50% - meaning there must be a reserve of spare receptors
is receptor reserve advantageous?
It means that there are large responses at lower concentrations of the drug meaning there could be less chance of S/E
What is furchgott modification?
Effect of drug - Response (=f - receptor number, occupancy, efficacy). It depends on 2 tissue factors (transduction, receptor number), and 2 drug factors (occupancy/affinity, intrinsic efficacy).
What are inverse agonists?
drug that produces the opposite response to the agonist
What is the difference between antagonists and inverse agonists?
antagonists - block the action of agonists - neutral effect on receptor
Inverse = block the actions of agonists but ALSO suppress agonist-independent activity.
What are 4 drug classifications?
Agonist - drug binds to receptor & produce response
Partial agonist - produces an effect LESS than the maximum
Antagonist - binds but does not cause activation
Inverse agonist - produces opposite response to agonist, blocks agonist and suppresses agonist independent activity.
