Receptor theory

Question 1

What is a drug

Answer 1

A chemical substance that is able to change the physiological function of the organism

Question 2

Name macromolecular drug targets

Answer 2

Enzymes
Transporter proteins
Ion channel proteins
Receptors (cell surface or intracellular)
Nucleic acids

Question 3

What is drug specificity

Answer 3

Refers to the different chemical structure/shape of a drug dictating the ability to bind/induce a response

Question 4

What are the two main models proposed for drug-receptor binding

Answer 4

Lock and key

Zipper

Question 5

Describe the lock and key model for drug-receptor binding

Answer 5

Receptor = lock; Agonist = key

Only holds up if the receptor/ligand have a specific, unchanging shape

Question 6

Describe the zipper model for drug-receptor binding

Answer 6

Drug molecule is flexible, binds to receptor in stages.

Occurs in some cases, but not every drug does this

Question 7

Give examples of bonds involved in drug-macromolecular binding

Answer 7

Covalent
Ionic
Hydrogen
Van der waals

Question 8

Discuss covalent bonds in the context of drug-macromolecular binding

Answer 8

Strongest
Irreversible
Can be useful for drugs to form because gives longer lasting effects (but can be bad if bad side effects). Not used for agonists

Question 9

Discuss ionic bonds in the context of drug-macromolecular binding

Answer 9

Strength varies. Stronger in hydrophobic environments.
Drugs stored in ionised salt states.
Important function groups - COOH, NH2, SH, phosphate (ionised at pH 7.4)

Question 10

What assumptions are the single occupancy theory based on

Answer 10

A measured biological response (E) is proportional to fractional occupancy (not the case with partial agonists)
The drug is not degraded by the system
Effect is seen by 1 drug molecule binding to 1 receptor molecule
Effect is measured when reaction has reached equilibrium

Question 11

Define agonist

Answer 11

A molecule that is able to bind to a receptor and induce a response

Question 12

Define partial agonist

Answer 12

As an agonist, but produces a sub-maximal effect

Question 13

Define intrinsic activity

Answer 13

The ability for a drug to produce an effect after binding

Question 14

Define spare receptor

Answer 14

Only a certain proportion of receptors need to be occupied to produce a maximal response. All others are Spare Receptors.

Question 15

How is intrinsic activity linked to the simple occupancy theory

Answer 15

Agonists and partial agonists have different intrinsic activity (f). Simple occupancy theory does not account for this so was adapted.

Question 16

What is the simple ‘occupancy theory’

Answer 16

Binding of a drug to an appropriate receptor/binding site is reversible, and extent determined by following the reversible equilibrium:
D + R DR
(forward rate = K1; the association rate constant)
(backward rate = K2; the dissociation rate constant)

Question 17

What is the criteria for hormone-receptor mediated events

Answer 17

Receptor must:
have structural/steric specificity for hormone
be saturable/limited
cell specific hormone/receptor binding
Have high affinity for the ligand at physiological concentrations
Once ligand binds to receptor a chemical event must occur

Question 18

If pH = pKa what is the degree of ionisation

Answer 18

50%

Question 19

Name major properties of receptors

Answer 19

Recognition (of ligand)
Saturability (finite no.)
Reversibility (non-covalent binding - H bonds etc)
Steroeoselectivity (only recognising one optical isomer)
Agonist specificity (structurally similar drugs should bind well)

Question 20

What shape is a log dose-response curve

Answer 20

Sigmoidal

Question 21

What is an EC50 value

Answer 21

The effective concentration of agonist needed to produce 50% of maximum response

Question 22

When the simple occupancy theory is accurate, what value is equal to EC50

Answer 22

Kd

Question 23

What type of agonist is not explained by the simple occupancy theory

Answer 23

Partial agonists.

Question 24

How is intrinsic activity measured

Answer 24

intrinsic activity = f.
Full agonists = 1
Antagonists = 0
Partial agonists > 0 and < 1

Question 25

How does a dose/response curve look different if there are spare receptors present

Answer 25

Much steeper increase as lower dose needed to produce Emax.

Question 26

Who incorporated 'spare receptors' into the occupancy theory

Answer 26

Stephenson.

Question 27

Which two factors is the size of the stimulus thought to depend on

Answer 27

``` Agonist fractional occupancy (spare receptor) Agonist efficacy (e) ```

Question 28

Describe how the efficacy of agonists can vary

Answer 28

Some agonists produce a varied response even when occupying the same number of receptors

Question 29

Contrast high- and lower- efficacy agonists

Answer 29

High - max resp while occupying low proportion of receptors | Low - Cannot activate to the same degree, can behave as partial agonists.

Question 30

Define 'super agonists'

Answer 30

Efficacy greater than the endogenous agonist

Question 31

Define 'silent antagonist'

Answer 31

Has affinity but no efficacy

Question 32

State the % Efficacy of different types of ligand

Answer 32

Super agonist >100 Full agonist =100 Partial agonist 0

Question 33

How can two different full agonists generate the same Emax with different efficacies

Answer 33

Different combinations of efficacies/spare receptor properties can give the same stimulus (Emax)

Question 34

What is the minimum efficacy required for an agonist to be 'full'

Answer 34

10 (arb units). This would require occupancy of whole receptor population.

Question 35

How does Emax/occupancy relate to EC50

Answer 35

If Emax is reached at a lower occupancy, EC50 will be lower (and vice versa)

Question 36

What does drug potency depend on

Answer 36

Kd and efficacy

Question 37

What happens when an antagonist binds to a receptor

Answer 37

Agonist binding/ transduction systems prevented | No activation of response

Question 38

What shape is a concentration-response curve

Answer 38

Rectangular hyperbolic

Question 39

What happens to the concentration-response curve in the presence of a competitive antagonist

Answer 39

Increased concentration needed to produce same response. Unchanged Emax

Question 40

What happens to the log concentration-response curve in the presence of a competitive antagonist

Answer 40

Both sigmoidal. Antagonist produces parallel shift to the right. Increased log concentrations needed. Unchanged Emax.

Question 41

How does a double reciprocal plot change when competitive antagonist is added

Answer 41

New straight line produced. Different x-axis intercept. Unchanged y-axis intercept

Question 42

What are dose ratios

Answer 42

Agonist concentrations needed to produce a given level of response in the absence/presence of increasing conc of antagonist

Question 43

What does a Schild Plot show

Answer 43

The relationship between the different dose ratios (Dr) and its corresponding antagonist concentration.

Question 44

What should a Schild Plot look like when from made from a competitive antagonist dose ratio

Answer 44

Slope = 1. Positive increase.

Question 45

What is the pA2 value

Answer 45

A value used to simply indicate the antagonist dissociation constant

Question 46

Give an example of a non-competitive antagonist

Answer 46

Ketamine. Antagonist of the NMDA glutamate receptor. | Nifedipine. Antagonist of VGCCs.

Question 47

Define indirect antagonism

Answer 47

Antagonist that binds to a site on a downstream signalling component that has no physical association with the agonist binding receptor.

Question 48

What happens to the concentration-response curve in the presence of a NON-competitive antagonist

Answer 48

Reduced Emax. EC50 unchanged.

Question 49

What happens to the log concentration-response curve in the presence of a competitive antagonist

Answer 49

Reduced Emax. EC50 unchanged

Question 50

How does a double reciprocal plot change when a NON-competitive antagonist is added

Answer 50

New line: X-axis intercept unchanged Y-axis intercept changed

Question 51

How does a reversible non-competitive antagonist affect the dose-response curve

Answer 51

Decreased Emax | EC50 unchanged

Question 52

Give an example of an irreversible competitive antagonist

Answer 52

Naloxazone. Mu-opioid receptor antagonist.

Question 53

How can some irreversible antagonists act like non-competitive antagonists

Answer 53

Can initially bind quickly and reversibly to the receptor. Covalent bonds form later. Seems like non-comp initially.

Question 54

Name an inverse agonists

Answer 54

Beta-carboline. Acts on the benzodiazepine binding site on the GABAa receptor.

Question 55

Name an agonist, inverse agonist and antagonist of the GABAa receptor

Answer 55

Agonist: Diazepam Inverse Agonist: Beta-carboline Antagonist: Flumazenil

Question 56

Describe the two state model

Answer 56

GPCRs may exist in two states. R - no Gs coupling. No cAMP. R* - GS coupling. cAMP. Some (not many) receptors exist as R* receptors

Question 57

Describe the two state model in the context of agonists, inverse agonists and 'pure' antagonists

Answer 57

Agonists: Prefer R* state Inverse agonists: Prefer R state 'Pure' Antagonists: no effect on equilibrium of R/R*

Question 58

What is cooperativity in the context of receptors

Answer 58

Some receptors have multiple binding sites where the affinity of the binding sites for a ligand is in/decreased upon binding of a ligand to a binding site.

Question 59

Name the two types of cooperativity (receptors)

Answer 59

Homotropic cooperativity | Heterotropic cooperativity

Question 60

Define homotropic cooperativity

Answer 60

When the molecule causing the cooperativity is the one that will be affected by it

Question 61

Define heterotropic cooperativity

Answer 61

Where a third substance causes the change in affinity (allosteric)

Question 62

Name some benefits of using allosteric modulators instead of orthosteric modulators

Answer 62

GPCR allosteric binding sites are not as conserved, so more selective. Decreased potential for toxic effects. If has little efficacy, can slightly in/decrease tissue response in presence of endogenous agonist.