Receptor Theory Flashcards
Binding, Affinity, Agonists and Antagonists
where do drugs bind?
to specific receptors
- The drug (ligand) with the higher affinity is more specific for that receptor
what 3 factors control drug binding? explain each
Speed of drug reaching receptor is diffusion controlled
electrostatic, hydrophobic, and hydrogen bonds allow drug to “fit” into binding site
Binding is a dynamic equilibrium in other words the drug does not remain bound forever
how do electrostatic forces impact drug binding?
the ligand (drug) and the receptor must have opposite charges to ensure they are attracted to one another
how do hydrophobic forces impact drug binding?
if the ligand (drug) is polar the receptor must also be polar
if the ligand is lipophilic the receptor must also be lipophilic
how does the “Shape” of molecule and binding site impact drug binding?
the drug must have the male shape when the recptor has the identical female shape so they fit together
- Just like certain keys only fit in certain locks
what is a ligand binding assay?
a laboratory procedure that measures the interaction between a ligand and a receptor
what is the word equation for a ligand binding assay?
L+R <–> LR
- where L is the ligand
- R is the receptor
- LR is the ligand-receptor complex
what is the binding constant or affinity constant?
a measure of how strongly the ligand and receptor bind to each other.
how is the binding constant measured?
It’s calculated using the equilibrium dissociation constant (Kd), which is the ratio of the concentrations of the ligand and receptor to the concentration of the ligand-receptor complex.
what does high affinity mean in terms of drug binding?
tightly fitting
what are non-specific receptor sites?
molecular sites that bind to ligands but are not designated as receptors
(will bind loosely)
- lots of them, with many different structures
L + R <–> LR shows what?
binding at equilibrium.
- the number of ligands binding = the number unbinding
explain the organ bath experiment
studying physiological effects of a piece of tissue in a nutritionally complete water bath.
- adding varying drugs then studing effects
what is a concentration effect curve?
- The potency of drugs is reflected in their position on a concentration-response curve - the further to the left the drug response curve lies, the more potent the drug.
how is the potency of a drug usually recorded?
The potency of a drug is usually expressed as the concentration of the drug required to achieve a half-maximal stimulation of the response (EC50).
define EC50
Concentration of a drug that causes half the maximal effect produced by that drug
how does EC50 explore drug selectivity?
Measuring EC50 (and/or the KD and Ki) against many (several to 100s!) receptors
what is an antagonist?
- a drug that binds to a receptor but does not activate (zero efficacy)
what is the function of an antagonist?
A drug that blocks the action of an agonist
- compete for receptor binding but do not activate thus blocking action of the agonist
what is the IC50?
concentration of antagonist to inhibit 50% an agonist-induced response
what is the IC50 dependant on?
on the assay conditions used
what does the IC50 not reveal?
the mechanism of the antagonist
what are the 3 possible antagonist mechanisms?
- competitive
- reversible
- non-competitive
what 2 things do pharmacologists want to do when measuring antagonist action?
- analyse mechanisms of antagonism
- determine the dissociation constant for antagonist binding to a receptor as a measure of affinity
how do pharmacologist measure antagonist action?
Concentration-response curves to an agonist in the presence of increasing antagonist concentrations
- Dose ratio
- Schild plot
why is it important to measure antagonist action?
Give indication of how body systems work, doses of drug required to exert effect, selectivity over other targets
what is the equation of dose ratio?
dose ratio = EC50+antagonist / EC50control
if the EC50 with antagonist > EC50 control what is the dose ratio?
“dose ratio” >1
slide 8?
define dose ratio
fold increase in agonist concentration needed to evoke a given response (normally EC50) in presence of antagonist
Increasing concentration of antagonist leads to …….
increased dose ratios
what is Ka?
association constant/affinity constant for agonist (1/Kd)
what is Kb?
KB the concentration of antagonist that binds to 50% of receptors in the absence of an agonist
what does the schild slope equal for a competative antagonist?
1
how can we estimate antagonist affinity (Kd)?
we can estimate antagonist affinity(KD) from CRC curves with antagonists
what does the Schild plot tell us?
Schild plot tells if an antagonist is competitive and if so, an estimate of its
affinity
for a competative anatagonist what else is the -log(Ka) (i.e. pKa) called?
pA2
define pA2 value
defined as the concentration of antagonist required to produce an agonist dose ratio = 2
what is pA2 a measure of for a competative antagonist?
For competitive antagonist this is a measure of affinity and potency
what are the 4 possible option if the schild plot slope doesn’t equal 1?
- Insurmountable antagonism
- Multiple binding sites
- Pharmacokinetic effects
- Allosteric interactions
what is an insurmountable antagonist?
in the presence of the antagonist no matter how much agonist you add you will never elicit the maximum response
true or false:
you can have both competative and non-competative irreversible antagonists
true
what type of drugs have many irreversible inhibitors?
drugs targeting enzymes
(Often in this context termed suicide inhibitors)
what is an allosteric antagonist?
a drug that binds to a receptor and reduces the ability of an agonist to activate the receptor
(reversable but not competitive)
what do bioassays tell us about antagonists?
- type of antagonist
- dissociation constant (affinity) for competative antagonists
Rank these competitive reversible antagonists from highest to lowest affinity/potency
Drug W logKB -7(M)
Drug X pKB 8.5
Drug Y KB 3.2 x10-9 M
Drug Z pKB 9
Z
X
Y
W
define efficacy
Efficacy is the ability of a drug to activate a receptor and cause a response (effect)
efficacy is the product of an …
agonist (A)
what must happen to a drug (agonist) before it causes an effect?
must first bind
what is binding of an agonist measured as?
affinity
what is the effect of the binding measured as?
efficacy
what is Emax?
the maxiumum response that an agonist can achieve
what is EC50?
the concentration agonist required to produce 50 % of the Emax – potency
what are partial agonists?
agonists that cannot evoke the maximal response that a tissue can produce
what is KD?
dissociation constant and is a measure of affinity
what is occupancy therefore dependant on from the fractional occupancy equation?
Occupancy is therefore dependent upon the affinity and concentration of the drug and explains binding curves
true or false:
receptor occupancy is always directly proportional to the response
false
- Receptor occupancy is not directly proportional to the response
- maximal response often obtained with <100% occupancy (see later)
what is efficacy determined by?
Efficacy is determined by Emax relative to full agonist in functional tests
- full agonist =1
- partial agonists <1
slide 9
what are the 4 drug classifications?
- agonist
- partial agonist
- antagonist
- inverse agonist
what is an agonist?
Drug that binds to a receptor and produces a response
what is a partial agonist?
Drug that produces an effect less than the maximum
what is an antagonist?
Drug that binds but does not cause activation
what is an inverse agonist?
Drug that produces the opposite response to the agonist
why does receptor occupancy not explain partial agonists?
as receptors occupied to the same extent
(the effect of a drug is not solely determined by how many receptors it occupies)
what are 3 key features of partial agonists?
- It has both agonistic and antagonistic properties.
- It can act as an agonist in the absence of a full agonist, producing some effect.
- It can act as an antagonist in the presence of a full agonist, reducing the full agonist’s maximal effect.
true or false:
Some drugs can produce their full effect without binding to all receptors.
true
- imagine you have 100 light switches in a room, but you only need to turn on 50 of them to make the room fully bright.
why do some drugs not need to bind to all receptors to produce the full effect?
even if not all receptors are occupied, the body magnifies the signal enough to give the full effect.
what 2 things does drug response depend on?
- occupancy
- efficacy
what determins drug type?
intrinsic activity factor (ß)
what ß value shows full agonist, partial agonist and antagonist?
ß=1 = full agonist
ß<1 = partial agonist
ß=0 = antagonist
what is the Modified Occupancy Theory?
explains that response is not just about receptor binding but also the drug’s ability to activate the receptor.
what type of clinical response do partial agonist produce?
Produce a submaximal response, meaning they activate the system but not fully.
what is one pro to partial agonists?
Cause less desensitization, reducing the risk of tolerance over time.
what can partial agonist be used as, as an alternative to antagonists?
Competitve inhibitors:
- Block full agonists by occupying receptors, but still provide some activation.
- Unlike antagonists, they do not completely shut down the system.
what is an example of a partial agonist?
- Buprenorphine
(pain relief)
define receptor reserve
Maximal response can be obtained with submaximal occupation
what does a concentration response curve show about receptor reserve?
Even if only half of the receptors are used, the effect can still be maximum, meaning there are extra receptors available that aren’t needed for the full response.
what does receptor reserve allow for?
allows for signal amplification
- meaning the tissue contributes to the effect, not just the receptor.
Changes in what can impact signal amplification?
Changes in protein expression can impact signal amplification.
what do lower drug concentrations reduce?
Lower drug concentrations reduce the likelihood of side effects.
what is the response of a drug dependent on?
- Two tissue factors (transduction, receptor number)
- Two drug factors (occupancy/affinity, intrinsic efficacy)
what are inverse agonists?
inverse agonists produce opposite effects to agonists, acting similarly to antagonists but with the opposite response.
inverse agonists led to the occupation theory being revised to have ….
According to this model, receptors can exist in either an active (R*) or inactive (R) state spontaneously.
what is the difference between antagonists and inverse agonists?
- antagonists prevent activation without affecting the receptor’s baseline activity
- inverse agonists actively reduce the receptor’s activity below its normal resting level.
