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RECEPTORS Flashcards

1
Q

How much of the genome approximately is gene causing?

A

10%

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2
Q

Most drugs are small molecules that target proteins. Give examples of some protein drug targets.

A 
Receptors
Ion channels
Enzymes
Transports
Microtubules
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3
Q

What are the ways in which a receptor might be classified?

A

Structure
Pharmacologically
Signalling

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4
Q

To be a good drug target, a receptor must be able to do what?

A

Recognise a very specific molecule.

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5
Q

How can drugs work in terms of receptor target?

A

Agonist - bring about a change in cell function
Inverse agonists - bind to the receptor and stabilise it from signalling
Anatagonists - bind to the receptor and do not evoke a response

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6
Q

How can drugs work in terms of ion channel targets?

A

You can use a drugs as a blocker to stop an ion channel function.
You can use a modulator to change the open probability of an ion channel.

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7
Q

How can drugs work in terms of enzyme targets?

A

You can use a drug as an enzyme inhibitor.
You can use a false substrate to crease an abnormal metabolite.
Prodrugs can be metabolised into the active drug by enzymes.

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8
Q

How can drugs work in terms of transporter targets?

A

You can inhibit/block the transporter from working.

You can use a false substrate so an abnormal compound accumulates.

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9
Q

Give other examples of targets that drugs can work on.

A

Colchicine interferes with the stability of microtubules - used to treat gout.
Paclitaxel is a chemotherapy drug -during division is stabilises microtubules so the cells cannot split.

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10
Q

What are the receptor families?

A
  1. Ligand gated ion channel (ionotropic receptors)
  2. GPCR (metabtropic receptors)
  3. Kinase linked receptors
  4. Nuclear receptors
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11
Q

What are the features of ligand gated ion channels?

A

They have a ligand binding site.
They have multiple TMSD
They are very fast acting
They have a pore

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12
Q

What are the features of GPCR?

A

They have a ligand binding site.
The have 7 TMSD
Often requires action of other proteins such as GTP binding protein

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13
Q

What are the features of kinase linked receptors?

A

They have a ligand binding site
They have 1 TMSD
They have a catalytic domain causing signalling cascade

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14
Q

What are the features of nuclear receptors?

A

They have a DNA binding domain (zinc fingers)

They have no TMSD as they are not located at the cell membrane.

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15
Q

The molecular architecture of ligand gated ion channels identifies distinct families. Name some examples.

A
  1. Cys Loop Type
  2. Ionotropic Glutamate Type
  3. P2X Type
  4. Calcium Release Type
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16
Q

What are the features of Cys Loop Type Ligand Gated Ion Channels?

A

Has 4 TMSD
Pentameric
Eg nACHR, GABA

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17
Q

What are the features of Ionotropic Glutamate Type Ligand Gated Ion Channels?

A

Tetrameric

Eg NMDA

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18
Q

What are the features of P2X Type Ligand Gated Ion Channels?

A

Has 2 TMSD
Trimeric
ATP ligand
Eg P2XR

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19
Q

What are the features of Calcium Release Type Ligand Gated Ion Channels?

A

Is intracellular (found of the ER)
Tetrameric
EG IP3R

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20
Q

Occupancy of a receptor by a drug molecule may or may not bring about activation of the receptor. Why is this?

A

Occupancy is goverened by affinity to the receptor and not whether the receptor is activated.

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21
Q

Activation is governed by efficacy. What is efficacy?

A

How well a drug activates a receptor to evoke a response.

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22
Q

What is affinity?

A

How well a drug binds to a receptor.

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23
Q

What is occupancy?

A

The proportion of receptors occupied will vary with drug concentration.
= no. receptors occupied/total no. of receptors available

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24
Q

A high occupancy in theory should produce a large response. Why is this not true?

A

In the case of an antagonist, no reponse is evoked.

In the case of an agonist, occupancy is not directly related to response - it is efficacy that affects response.

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25
What is one way to measure occupancy (and thereby deduce affinity?)
Radioligand Binding Assay.
26
What does a Radioligand Binding Assay involve?
Measuring a radioactively labelled ligand binding to a protein target.
27
What is the process of radioligand binding assays?
1. Sample that contains protein target of interest. 2. Radioactive molecule version of the drug you want to test. 3. Incubate mixture until it reaches equilibrium. 4. Filter and wash away all non bound (excess) ligand 5. Measure the radioactivity left behind ie measure the radioactive drug bound to the receptors
28
Most ligands bind specifically and non-specificially to its target/filter paper/ test tube etc. This means that in rinsing the filter paper, you are only removing non bound ligand. What is left behind is specifically bound ligand and non specifically bound ligand. How do you discriminate between specific and non specific binding?
A first set of test tubes is set up containing the tissue and radiolabelled ligand. A second set of test tubes is set up containing the radiolabelled ligand and excess, cold unlabelled ligand. The radioligand cannot compete with the the unlabelled ligand and is displaced from the recognition sites by cold ligand. The radioactivity in Test Tube 1 will contain specific and non specific radioactive binding Test Tube 2 will contain only non specific radiobinding. From this we can calculate the specific radiobound ligand.
29
What must be considered for a radioligand binding assay?
The purity, degradation, and labelling of the radioligand. The tissue and incubation conditions. Separating bound from free. Data analysis.
30
How can you prevent degradation of the radioligand?
1. Free radical scavenger. 2. Store at low temperatures. 3. Avoid light. 4. Incorporation of antioxidant.
31
What are the advantages of labelling with 3H?
It does not affect the ligand. Long half life. Good stability.
32
What are the diadvantages of labelling with 3H?
Specialised labs are needed to work with 3H. | Labelling is expensive and difficult.
33
What are the advantages of labelling with 125I?
Labelling is easy and cheap. | Labelling is safer.
34
What are the disavantages of labelling 125I?
Degrades more quickly. | Interferes with the ligand more.
35
We want to preserve and purify the POI so we can measure accurately. Cells in a sample may be broken down affecting the protein of interest. How can we limit this?
1. Adding protease inhibitors. 2. Keeping the cell whole could prevent contact with natural occurring proteases. 3. Low temperatures to prevent/slow protease activity.
36
The radioligand binding assay depends on the mixtures reaching equilibrium. The time to reach equilibrium will change depending on the rate of the forwards and backward ratio. If a ligand has a low affinity ie has a fast back reaction and separates quickly, it is difficult to measure. Ligand binding is there more suited to what kind of molecule.
High affinity molecules.
37
If the Kd is small, way can be said about the affinity?
The affinity is high and therefore is suitable for a radioligand binding assay.
38
What are the axes and plots of a radioligand binding curve?
x= concentration drug y=radioactivity plots: total binding (test tube 1) non specific binding (test tube 2)
39
What is the scatchard equation?
Bound/Free = (Total Binding - Specific Binding)/Kd
40
What does the Langmuir Equation describe?
The relationship between relationship between receptor occupancy, affinity and drug concentration.
41
What is the Langmuir Equation?
Bound = (Total Binding*Conc)/(Conc+Kd)
42
The concentration of drug at which 50% of receptors are occupied is also known as what?
Kd = the affinity constant
43
The higher the affinity for its receptor, the ...................... the concentration of drug will be needed for a given level of occupancy.
Lower
44
Kd =
Back Reaction / Forwards Reaction
45
What is the equation for a Scatchard Plot?
Bound/Free = (Total Binding - Specific Binding)/Kd
46
How can you measure the slope of a Scatchard Plot?
-1/Kd
47
What does the x axis intercept?
Total binding
48
What is the Kd?
A measure of affinity
49
Why do we need to measure receptors?
To define receptors To understand the rate of drug/ligand action To find how many receptors are in a given tissue To find how receptor numbers change in disease.
50
What does agonist potency depend on?
Affinity and efficacy.
51
Agonists have an efficacy of what?
=1
52
Antagonists have an efficacy of what?
0
53
Partial agonists have an efficacy of what?
<1
54
What is the EC50?
The effective concentration at which you will get 50% of the maximal response.
55
Why is EC50 not = Kd
In the case of most agonists, to elicit and maximal response, not all receptors need to be occupied. This may be down to a receptor reserve, spare receptors.
56
What is another reason that EC50 does not = Kd in most agonists?
The curve response may depend on the biology of the cell and depend on what receptor is activated. For example, GPCR have an amplification signal.
57
What equation can be used to fit concentration response curves?
The Hill Equation
58
How can be use EC50 as a measure of agonist potency?`
When compared with multiple drugs, the drug with the lowest EC50 will be the most potent.
59
Not all agonists have an efficacy =1 | Agonists vary in efficacy between 0 and 1. If that is the case, how can we measure EC50?
EC50 is based on 50% of the response that a particular drug can elicit, although it may not be 100% response potential of the tissue it is affecting.
60
You can use a dose response curve to work out the affinity of a partial agonist. If response is not governed by affinity, how can this be?
A partial agonist must have 100% occupancy for it to elicit its maximum response. Therefore the EC50 = Kd and is the only drug type that you can use a dose reponse curve to measure affinity.
61
What are the properties that determine the effect of a drug in a living system?
Specificity Affinity Efficacy
62
What is the definition of antagonism?
A drug that prevents the response of an agonist.
63
What are the classes of antagonism?
1. Chemical 2. Pharmacokinetic 3. Physiological 4. Non- competitive 5. Competitive
64
What is chemical antagonism?
When substances combine in solution to form a complex so that the effect of the active drug is lost.
65
What is pharmacokinetic antagonism?
Any drugs that lowers the concentration of an active drug by affecting its ADME
66
What is physiological antagonism?
The interaction of two drugs with two opposing actions in the body.
67
What is non competitive antagonism?
Prevents the action of an agonist but acting downstream of the agonist binding site.
68
What is competitive antagonism?
Reduces the occupancy of agonist by binding to the receptor. Reversible antagonism can be overcome but increasing the concentration of the agonist. Irreversible antagonism is permanent as the antagonist forms a covalent bond with the receptor.
69
Competitive reversible antagonistm can be overcome by increasing agonist concentration. These results can be show on a concentreation response curve plotting what?
``` x= agonist concentration y= response plots= agonist alone, increasing concentrations of antagonist ```
70
The concentration response curve of an agonist and competitive antagonist shifts to the right as the amount of antagonists increases. What happens to the response?
The maximum response stays the same because it is a competitive antagonist.
71
We can measure the shift in the dose response curve at a given concentration of antagonist. What is this called?
The Dose Ratio.
72
How is the Dose Ratio measured?
DR= concentration of agonist in presence of antagonist/concentration of agonist in absence of antagonist
73
What is a Schild Analysis?
A measure of antagonist affinity, relationship between dose ratio and agonist concentration.
74
How can the dose ratio also be measured?
DR=(Concentration of antagonist/Kd)+1 | the DR is always calculated at 2 this means that the KD=concentration of antagonist
75
How is a Schild analysis plotted?
On a linear scale but the values logged. x=log10 antagonist y=log10 (DR-1)
76
What does the x intercept of a Schild Plot show?
when x=0, the pA2 is the negative value of this number. The pA2 is the measure of affinity. pA2=-logKd
77
What does the pA2 actually stand for?
The molar concentration of antagonist that gives a dose ration of 2.
78
A pA2 of 6 gives a Kd value of what?
1x10-6
79
Irreversible antagonism is time-dependent. As the concentration of drug increases, what happens to the maximum?
The maximum response is reduced due to the continued presence of the antagonist. This cannot be reversed by increasing agonist concentration. Maximum response can initially be attained due to the presence of spare receptors but over time the reserves are used up to so the maximum response will decrease.
80
What is tachphylasxis?
Desensitisation
81
Why might the effect of a drug decline over time when given continuously or repeatedly?
Loss of receptors from the surface (internalisation) Change in the receptor itself (phosphorylation) Exhaustion of mediators Increased metabolic degradation/extrusion Physiological adaptation

PHYSIOLOGY & PHARMACOLOGY (8 decks)

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