Receptor theory

Question 1

What is KD?

Answer 1

Dissociation constant - measure if affinity. Concentration of ligand the binds to 50% of the receptors. The smaller the KD = the higher the affinity

Question 2

Relationship between KD and affinity?

Answer 2

Smaller KD = higher affinity

Question 3

What is the Ki value?

Answer 3

Concentration of competing ligand required to displace 50% of the specific binding of radioligand

Question 4

What affects Ki values?

Answer 4

the assay conditions and dependent on the concentration of ligand

Question 5

relationship between affinity and Ki?

Answer 5

Highest affinity has the lowest Ki value

Question 6

why are higher affinities desired?

Answer 6

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

Question 7

What is an agonist?

Answer 7

bind to receptors and Activate them to initiate a response

Question 8

Define EC50

Answer 8

Concentration of drug that causes half the maximal effect produced by the drug (agonist) - measure of potency

Question 9

Define antagonist

Answer 9

Drug that binds to a receptor but does not activate it - zero efficacy. Blocks the action of the agonis & competes for receptor binding.

Question 10

Define IC50

Answer 10

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.

Question 11

what information does the IC50 NOT provide?

Answer 11

NO info on the mechanism e.g. if it is competitive, reversible, non competitive etc

Question 12

Dose ratio equation?

Answer 12

EC50 + [antagonist] / EC50 of control

Question 13

What happens to the agonist in presence of an antagonist ?

Answer 13

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

Question 14

What happens when we add more competitive surmountable antagonist?

Answer 14

Reduces the amount of receptor-agonist complex and thus less effect.

Question 15

what does surmountable mean?

Answer 15

increase in antagonist pushes equilibrium to get less agonist effect

Question 16

In the presence of what type of antagonist will you eventually get the agonist maximal response?

Answer 16

Competitive surmountable antagonist

Question 17

Define dose ratio

Answer 17

The fold increase in agonist concentration that is needed to evoke a given response (normally EC50) in the presence of an antagonist

Question 18

What does antagonist do to the dose ratio?

Answer 18

Increases it

Question 19

What does a dose ratio of 2 mean?

Answer 19

Twice as much agonist is required to produce the same response

Question 20

What does a straight line = 1 on schild plot show?

Answer 20

we have a competitive antagonist, it also gives us the log KB

Question 21

Define KB

Answer 21

The concentration of antagonist that binds to 50% of receptors - a measure of affinity

Question 22

Relationship between KB and affinity, and PKB and affinity (antagonist)

Answer 22

The lower theKB = higher the affinity of antagonist.
PKB is the negative of KB so the higher the PKB = higher the affinity.

PKB = -logKB

Question 23

how do you calculate PKB?

Answer 23

-logKB

Question 24

What is PKB also referred to as?

Answer 24

The PA2 value - measure of affinity & potency.

The concentration of antagonist required to produce an agonist dose ratio of 2.

Question 25

Give an example of a competitive antagonist

Answer 25

Candesartan - anti-hypertensive/heart failure - an antagonist of angiotensin II = reduce peripheral resistance - vasodilation

Question 26

When is the PKB/PA2 value only a valid measure of affinity?

Answer 26

ONLY if the antagonist is competitive and reversible (slope = 1 schild)

Question 27

2 types of insurmountable antagonism

Answer 27

Irreversible | Allosteric

Question 28

Insurmountable antagonism Definition

Answer 28

In the presence of antagonist, no matter how much agonist you add, you will NEVER elicit the maximum response

Question 29

what is non-competitive allosteric antagonism?

Answer 29

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.

Question 30

Compare competitive and non-competitive antagonism

Answer 30

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

Question 31

2 types of irreversible antagonism

Answer 31

competitive - compete for same binding site. | Non competitive - lock receptor into irreversible state

Question 32

are irreversible antagonists used clinically?

Answer 32

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.

Question 33

3 things that bioassays tell us about antagonists?

Answer 33

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

Question 34

Define efficacy

Answer 34

The ability of a drug to activate a receptor and cause a. response - response is dependent on amount of receptors occupied.

Question 35

What is a partial agonist?

Answer 35

Some agonists cannot evoke the maximal response that a tissue can produce = lower Emax Full agonist = 1 Partial agonist = <1

Question 36

what is potency based on?

Answer 36

EC50 value

Question 37

Why doesn't receptor occupancy theory explain partial agonists?

Answer 37

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

Question 38

How does intrinsic activity explain partial agonists? - modified occupancy theory

Answer 38

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

Question 39

Advantages of partial agonists as drugs

Answer 39

- submaximal tissue response - does not stimulate fully the system - Less desensitisation - can also act as competitive inhibitors of full agonists

Question 40

Drug that is a partial agonist

Answer 40

Buprenorphine - For opioid dependence and pain relief (Temgesic) Partial agonist at opioid receptors - don't get full response desensitisation

Question 41

what is the theory of receptor reserve?

Answer 41

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

Question 42

is receptor reserve advantageous?

Answer 42

It means that there are large responses at lower concentrations of the drug meaning there could be less chance of S/E

Question 43

What is furchgott modification?

Answer 43

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).

Question 44

What are inverse agonists?

Answer 44

drug that produces the opposite response to the agonist

Question 45

What is the difference between antagonists and inverse agonists?

Answer 45

antagonists - block the action of agonists - neutral effect on receptor Inverse = block the actions of agonists but ALSO suppress agonist-independent activity.

Question 46

What are 4 drug classifications?

Answer 46

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.