F7. Affinity, quantifying drug action Flashcards
what is an agonist?
reproduces the effects of endogenous messenger
what is an antagonist?
blocks the effects of the endogenous messenger
what is receptor antagonism?
antagonist physically binds to receptor- most common
what is pharmacokinetic antagonism?
The drug reduces the agonist drug concentration at the site of action e.g. by altering its liver metabolism
what is physiological antagonism?
The physiological actions of the two drugs oppose each other e.g. acetylcholine and noradrenaline on heart rate
what is a feature of new “antibody” therapies?
the drug combines with the stimulating messenger to inactivate it- a type of antagonism
what is affinity?
the ability of a drug to bind to its receptor
what is efficacy?
the ability of a drug, once bound, to activate the receptor by a conformational change
Describe agonists which bind and activate receptors?
they have affinity and efficacy
Describe antagonists which prevent agonist activation
receptor antagonists only have affinity and not efficacy
Drug binding obeys the law of mass action which is?
rates of binding are proportional to concentration
forward rate =
Kon[D][R]
Kon= association rate constant
reverse rate =
Koff[DR]
Koff= dissociation rate constant
At dynamic equilibrium?
forward rate= reverse rate
Kon[D][R]= Koff [DR]
KD (equilibrium dissociation constant)=?
[D][R]/[DR]
one note
what is D’s receptor occupancy (a) at a given concentration?
a= [D]/ [D] + KD
one note for working out
If the concentration of D equals its KD, how many receptors are occupied?
a= 0.5
so KD can also be defined as the drug concentration needed to occupy 50% of the molecular target at equilibrium i.e a measure of its binding affinity
-working out on one note
how can we measure KD?
radioligand binding:
-direct measurement of drug-target interactions using a radiolabelled drug probe
-we can quantify the amount of radiolabelled drug bound to its target (for example in a cell preparation), by counting the radioactivity bound to the assay sample
what are the different types of binding studies?
-Saturation analysis: obtains the affinity (KD) of the radiolabelled drug
-Competition analysis: obtains the affinity (KD) of any unlabelled drug for its target,
using an experiment when this drug competes for radioligand binding.
KD can also be known as…
Ki and Kb
pKD =?
-log10KD (compare to pH= -log10[H+]
pA2=?
-log10KD (used for a particular type of functional analysis)
what is KA?
affinity constant when used for drug-receptor interactions= 1/KD (units concentration-1 e.g nm-1)
why is KD useful?
-In drug discovery, changes in compound structure must be
related to their effects on activity at the molecular target.
-For receptors and other targets, measuring affinity as KD is a quick and convenient way of doing this.
Describe the difference in affinity between salbutamol (1uM) and formoterol (0.01uM) for airway B2 adrenoreceptors?
-Formoterol has a 100 fold higher affinity for airway adrenoreceptors than salbutamol
-When comparing
concentration
measurements (KD) we take the ratio
1 / 0.01 = 100
Describe the selectivity of formoterol compared to salbutamol when the concentration (KD) for heart B1 adrenoceptors in salbutamol is 10um and for formoterol is 1um
Formoterol is more selective than salbutamol for airway cf heart adrenoceptors
compare the B2/B1 selectivity for salbutamol
10 fold
compare the B2/B1 selectivity for formoterol
100 fold
