Drug Targets

Question 1

What is efficacy?

Answer 1

The ability to create a signal by binding to a receptor. Drugs with zero efficacy block receptors when they bind

Question 2

What is selectivity?

Answer 2

Preferential binding to certain subtypes leads to a greater effect at that subtype than others. Lack of selectivity can lead to unwanted effects

Question 3

Ionotropic receptors

Answer 3

Very fast (ms)
Binding of agonist causes conformational change in receptor too

Question 4

G-protein coupled receptors

Answer 4

fast (s)
beta alpha and gamma units stuck together. When inactive they have GDP when active bind to GTP and alpha subunit goes off by self

Question 5

What are Gi Gq and Gs?

Answer 5

Gi = inhibitory
Gs = Stimulatory
Gq = reacts with phospholipase C (to facilitate SMC contraction)

Gi and Gs can be bidirecitonal so different receptors can exert opposing effects on the target enzyme

Question 6

Catalytic recpetors

Answer 6

Minutes/days
Growth factors and hormones
receptors usually trigger a kinase cascade

Question 7

What are two important Catalytic pathways?

Answer 7

Ras/Raf/MAp kinase - cell differentiation

Jak/Stat - inflammation

Question 8

Intracellular recpetors

Answer 8

hours/days long lasting
steriod hormones
Always invovle changes in gene transcription
Bind to DNA
needs to be lipid soluable

Question 9

What is EC50?

Answer 9

the measure of agaonist potency. The lower the EC50 the greater the potency

Question 10

What is pD2?

Answer 10

The -ve log of EC50

Question 11

What is pA2?

Answer 11

-ve log of the concentration that shifts the curve two-fold

Question 12

Competitive reversible antagonism

Answer 12

competes directly with the agonist for binding to the receptor
Parallel rightwards shift of the curve

Question 13

What is the equation for Pa2?

Answer 13

pA2x + log(x-1)

x = EC50 (presence of agonist)/EC50(absence of agonist)
pAx = -ve log conc (M) of the antagonist

Question 14

Competitive Irreversible Antagonism

Answer 14

Competes directly with the agonist for binding but binds with greater affinity (normally convalantly)
Causes a non parallel rightward shift of the concentration response curve (depresssion in the maximal response)

Question 15

What is pD2’

Answer 15

Potency measure of irreversible antagonism and non competitive antagonism
A measure of how good and antagonist is at depressing the curve

Question 16

What is the Spare receptor theory?

Answer 16

Agonist does not have to bind to all receptors to cause a response so there is enough for antagonist to bind and you still get a good response

Question 17

Non competitive antagonism

Answer 17

Interfere with the signal pathway
do not bind to same receptor as against
on parallel rightward shift and depression in maximal response
pD2’

Question 18

Physiological antagonism

Answer 18

Occurs when two agonists working at different receptors have opposing actions
e.g histamine causing bronchoconstriciton
adrenaline causing bronchodilation

Question 19

Partial agonists

Answer 19

Do not elicit a maximal resposne so the ir efficacy is less than 1.
Can act as antagonists to full agonists
Crossover on the conc response curve as they can help initially

Question 20

Inverse angonists

Answer 20

Some receptors are naturally active and inverse agonists will turn the receptors off

Question 21

Receptor Plasticity (regulation of receptors)

Answer 21

Changes in receptor state
Exhaustion of mediators
Changes in receptor population

Question 22

Receptor state changes

Answer 22

Rapid pronounced desensitisation of metabotropic receptors due to phosphorylation
Heterologus - one agonist desensitizes a completely different agonist. Often invovles protein kinase A/C

Question 23

Receptor population changes

Answer 23

Chronic agonist administration can lead to down regulation. Continued desentitisation leads to cell removing receptors from membrane.

Chronic antagonist administration can lead to upregulation as cell sends out more receptors to ‘find’ agonist

Question 24

The clinical effects of population changes in tricyclic antidepressents

Answer 24

the therapeutic effect fo theses takes 2-4 weeks as cell starts to down regulate receptors in response to increased dopamine so therefore there is no obvious change

Question 25

Enzymes as targets

Answer 25

e.g COX for inflammation and ACE for hypertension

Question 26

COX 2 selective inhibitors

Answer 26

Are selective to only inhibit COX 2 not COX1 so don’t lead to GI problems

Question 27

Drugs which interact with carrier proteins

Answer 27

e.g drugs that act on monoamine NT uptake protein to take monoamines back into pre synaptic neuron such as Fluoxetine as an antidepressant