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A Quantitative Pharmacology > Receptor theory > Flashcards

Receptor theory Flashcards

1
Q

What is a drug

A

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

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2
Q

Name macromolecular drug targets

A 
Enzymes
Transporter proteins
Ion channel proteins
Receptors (cell surface or intracellular)
Nucleic acids
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3
Q

What is drug specificity

A

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

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4
Q

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

A

Lock and key

Zipper

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5
Q

Describe the lock and key model for drug-receptor binding

A

Receptor = lock; Agonist = key

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

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6
Q

Describe the zipper model for drug-receptor binding

A

Drug molecule is flexible, binds to receptor in stages.

Occurs in some cases, but not every drug does this

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7
Q

Give examples of bonds involved in drug-macromolecular binding

A

Covalent
Ionic
Hydrogen
Van der waals

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8
Q

Discuss covalent bonds in the context of drug-macromolecular binding

A

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

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9
Q

Discuss ionic bonds in the context of drug-macromolecular binding

A

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

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10
Q

What assumptions are the single occupancy theory based on

A

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

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11
Q

Define agonist

A

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

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12
Q

Define partial agonist

A

As an agonist, but produces a sub-maximal effect

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13
Q

Define intrinsic activity

A

The ability for a drug to produce an effect after binding

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14
Q

Define spare receptor

A

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

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15
Q

How is intrinsic activity linked to the simple occupancy theory

A

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

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16
Q

What is the simple ‘occupancy theory’

A

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)

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17
Q

What is the criteria for hormone-receptor mediated events

A

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

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18
Q

If pH = pKa what is the degree of ionisation

A

50%

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19
Q

Name major properties of receptors

A

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)

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20
Q

What shape is a log dose-response curve

A

Sigmoidal

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21
Q

What is an EC50 value

A

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

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22
Q

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

A

Kd

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23
Q

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

A

Partial agonists.

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24
Q

How is intrinsic activity measured

A

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

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25
Q

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

A

Much steeper increase as lower dose needed to produce Emax.

26
Q

Who incorporated ‘spare receptors’ into the occupancy theory

A

Stephenson.

27
Q

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

A 
Agonist fractional occupancy (spare receptor)
Agonist efficacy (e)
28
Q

Describe how the efficacy of agonists can vary

A

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

29
Q

Contrast high- and lower- efficacy agonists

A

High - max resp while occupying low proportion of receptors

Low - Cannot activate to the same degree, can behave as partial agonists.

30
Q

Define ‘super agonists’

A

Efficacy greater than the endogenous agonist

31
Q

Define ‘silent antagonist’

A

Has affinity but no efficacy

32
Q

State the % Efficacy of different types of ligand

A

Super agonist >100
Full agonist =100
Partial agonist 0

33
Q

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

A

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

34
Q

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

A

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

35
Q

How does Emax/occupancy relate to EC50

A

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

36
Q

What does drug potency depend on

A

Kd and efficacy

37
Q

What happens when an antagonist binds to a receptor

A

Agonist binding/ transduction systems prevented

No activation of response

38
Q

What shape is a concentration-response curve

A

Rectangular hyperbolic

39
Q

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

A

Increased concentration needed to produce same response. Unchanged Emax

40
Q

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

A

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

41
Q

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

A

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

42
Q

What are dose ratios

A

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

43
Q

What does a Schild Plot show

A

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

44
Q

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

A

Slope = 1. Positive increase.

45
Q

What is the pA2 value

A

A value used to simply indicate the antagonist dissociation constant

46
Q

Give an example of a non-competitive antagonist

A

Ketamine. Antagonist of the NMDA glutamate receptor.

Nifedipine. Antagonist of VGCCs.

47
Q

Define indirect antagonism

A

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

48
Q

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

A

Reduced Emax. EC50 unchanged.

49
Q

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

A

Reduced Emax. EC50 unchanged

50
Q

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

A

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

51
Q

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

A

Decreased Emax

EC50 unchanged

52
Q

Give an example of an irreversible competitive antagonist

A

Naloxazone. Mu-opioid receptor antagonist.

53
Q

How can some irreversible antagonists act like non-competitive antagonists

A

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

54
Q

Name an inverse agonists

A

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

55
Q

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

A

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

56
Q

Describe the two state model

A

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

57
Q

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

A

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

58
Q

What is cooperativity in the context of receptors

A

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.

59
Q

Name the two types of cooperativity (receptors)

A

Homotropic cooperativity

Heterotropic cooperativity

60
Q

Define homotropic cooperativity

A

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

61
Q

Define heterotropic cooperativity

A

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

62
Q

Name some benefits of using allosteric modulators instead of orthosteric modulators

A

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.

A Quantitative Pharmacology (4 decks)

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