F7. Affinity, quantifying drug action

Question 1

what is an agonist?

Answer 1

reproduces the effects of endogenous messenger

Question 2

what is an antagonist?

Answer 2

blocks the effects of the endogenous messenger

Question 3

what is receptor antagonism?

Answer 3

antagonist physically binds to receptor- most common

Question 4

what is pharmacokinetic antagonism?

Answer 4

The drug reduces the agonist drug concentration at the site of action e.g. by altering its liver metabolism

Question 5

what is physiological antagonism?

Answer 5

The physiological actions of the two drugs oppose each other e.g. acetylcholine and noradrenaline on heart rate

Question 6

what is a feature of new “antibody” therapies?

Answer 6

the drug combines with the stimulating messenger to inactivate it- a type of antagonism

Question 7

what is affinity?

Answer 7

the ability of a drug to bind to its receptor

Question 8

what is efficacy?

Answer 8

the ability of a drug, once bound, to activate the receptor by a conformational change

Question 9

Describe agonists which bind and activate receptors?

Answer 9

they have affinity and efficacy

Question 10

Describe antagonists which prevent agonist activation

Answer 10

receptor antagonists only have affinity and not efficacy

Question 11

Drug binding obeys the law of mass action which is?

Answer 11

rates of binding are proportional to concentration

Question 12

forward rate =

Answer 12

Kon[D][R]
Kon= association rate constant

Question 13

reverse rate =

Answer 13

Koff[DR]
Koff= dissociation rate constant

Question 14

At dynamic equilibrium?

Answer 14

forward rate= reverse rate
Kon[D][R]= Koff [DR]

Question 15

KD (equilibrium dissociation constant)=?

Answer 15

[D][R]/[DR]
one note

Question 16

what is D’s receptor occupancy (a) at a given concentration?

Answer 16

a= [D]/ [D] + KD
one note for working out

Question 17

If the concentration of D equals its KD, how many receptors are occupied?

Answer 17

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

Question 18

how can we measure KD?

Answer 18

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

Question 19

what are the different types of binding studies?

Answer 19

-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.

Question 20

KD can also be known as…

Answer 20

Ki and Kb

Question 21

pKD =?

Answer 21

-log10KD (compare to pH= -log10[H+]

Question 22

pA2=?

Answer 22

-log10KD (used for a particular type of functional analysis)

Question 23

what is KA?

Answer 23

affinity constant when used for drug-receptor interactions= 1/KD (units concentration-1 e.g nm-1)

Question 24

why is KD useful?

Answer 24

-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.

Question 25

Describe the difference in affinity between salbutamol (1uM) and formoterol (0.01uM) for airway B2 adrenoreceptors?

Answer 25

-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

Question 26

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

Answer 26

Formoterol is more selective than salbutamol for airway cf heart adrenoceptors

Question 27

compare the B2/B1 selectivity for salbutamol

Answer 27

10 fold

Question 28

compare the B2/B1 selectivity for formoterol

Answer 28

100 fold