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PA10315 COPY > Receptors 2 > Flashcards

Receptors 2 Flashcards

1
Q

What is neurotransmission?

A

Chemical communication and therefore has a central role in almost every regulatory mechanism in our body.

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2
Q

Who was the receptor concept found by?

A

John Newport Langley in 1905.

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3
Q

How was the receptor concept found?

A
  1. Nicotine was applied to frog skeletal muscle
  2. It was found that the muscle only contracted when placed at the joint between the nerve and the muscle (motor end plate).
  3. When it was applied to the nerve itself it had no effect
  4. Suggested that receptors were switches that received and generated signals, and which could be activated or blocked by specific molecules.
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4
Q

Who originated the quantitative receptor theory?

A
  1. Alfred J Clark - it applied chemical laws to biological ideas.
  2. Suggested that measurable drug-evoked responses in tissues resulted from the unimolecular interaction of the drug and a substance on the cell surface.
  3. Meant interaction between drug and cell was very specific
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5
Q

What is a receptor?

A

A macromolecule that combines with a drug in order to produce effects.

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6
Q

How do drugs modify the function of different organ systems?

A
  1. A pharmacodynamic interaction between the drug and the recognition system for that drug.
  2. Organ selectivity determined by the biological recognition unit for the drug = receptor.
  3. only acts on an organ if they have receptors for it
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7
Q

How can the response of muscle to a drug be measured?

A
  1. A Kymograph (made by Matteucci) can record variations in muscular and physiological processes.
  2. It was based on a rotating drum that was smoked with benzene and a scribe scratched a recording of the experiment.
  3. Used to be used to measure smooth muscle contraction
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8
Q

What is an agonist response?

A
  1. A response in which the drug produces a response.
  2. Ligand (drug) binds to binding site/domain/loci of receptor to form a drug receptor complex
  3. to produce a response as the drug elicits a stimulus in the receptor- agonists (drugs which produce a response)
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9
Q

Why is a graph of concentration against response not useful for pharmacologists?

A

Only the lower concentrations of the drug are useful - hard to see from this type of graph.

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10
Q

What graph is more useful?

A
  1. A log scale of concentration - a sigmoid graph is produced and the EC50 can be calculated by drawing a line at the 50% reponse.
  2. The log concentration transforms curve from rectangular parabola to sigmoid curve
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11
Q

What can EC50s be used for?

A
  1. Concentration of drug required to induce 50% maximal response
  2. They can be compared to work out how much more potent a certain drug is compared to another.
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12
Q

What is pEC50?

A

-log(EC50), measures drug potency.

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13
Q

What is intrinsic efficacy?

A
  1. The ability of a drug to stimulate tissue

2. The ability of a molecule to force a receptor into its active state, which is the state leading to cellular response.

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14
Q

What are antagonists?

A
  1. If no stimulus is elicited than no response- antagonists (drugs which produce no response and block responses induced by agonists).
  2. Have affinity for receptor but no intrinsic efficacy. (ability to produce response)
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15
Q

What do antagnonists do the potency of agonists?

A

They reduce the potency so larger doses are required for the same effects.

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16
Q

What is a competitive antagonist?

A

When the antagonist competes for the same site of the agnonist.

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17
Q

What are partial agonists?

A

Ligands that show some agonist activity but do not produce full responses and block responses produced by full agonists at the receptor.

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18
Q

Simplify the term for a strong partial agonist.

A

A strong agonist and a weak antagonist.

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19
Q

Simpify the term for a weak partial agonist.

A

A weak agonist and a strong antagonist.

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20
Q

What is affinity?

A

The ability of a drug to bind to a receptor.

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21
Q

What is potency?

A

A measure of drug activity expressed in terms of the amount required to produce an effect of given intensity.

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22
Q

What gives potency?

A
  1. The combined effects of affinity and efficacy.
  2. Depend on chemical properties of molecule and type and strength of interactions with receptor
  3. If interactions facilitate binding of receptor- high affinity
  4. If interactions facilitate function of receptor- high intrinsic efficacy
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23
Q

What forces control affinity?

A
  1. Thermodynamic
  2. Chemical forces- (vary depending on distance between drug and receptor - electrostatic, hydrogen, van der Waals, hydrophobic).
  3. Drug resides within a protein binding pocket in a position of minimal free energy- then causes either blockade or activation depending on if agonist or antagonist
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24
Q

What is the law of mass action?

A
  1. The rate of reaction is proportional to the product of the concentrations of the reactants.
  2. At equilibrium the forward and reverse rates are equal.
  3. Thus, KA is a concentration and quantifies affinity
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25
Q

What is receptor occupancy?

A

The portion of receptors bound to the ligand.

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26
Q

What is kd and how can you find it ?

A
  1. The ligand concentration that gives 50% of receptor occupancy.
  2. KD values are used to compare affinity of ligands and can be measured for antagonists as well
  3. Can plot specifically bound on y and x-axis as log scale get sigmoid curve and can find KD- at 50 on y
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27
Q

what did langley conclude from his experiments

A

Ach was combining with a ‘receptive’ substance in the motor end plate region (receptor!)

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28
Q

4 kinds of drug targets

A
  1. enzymes
  2. carrier molecules
  3. ion channels
  4. receptors
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29
Q

without a stimulus

A

no response, but still formation of drug-receptor complex

30
Q

how can the result of a drug-receptor interaction be measured?

A
  1. drugs labelled with one or more radioactive atoms-
  2. incubate samples of tissues with various concentrations of radioactive drug
  3. Increase concentration until saturation of receptors
  4. Gives total amount of binding in system and non-specific binding
  5. Difference between them gives amount specific binding
  6. biological response can be plotted as concentration-response curve
31
Q

What is EC50

A
  1. concentration of a drug required to elicit 50% maximal response
32
Q

what can’t concentration-effect graphs show

A
  1. affinity of agonists, because response is not directly proportional to receptor occupancy
  2. Arises because max response produced when occupancy not 100%
  3. in this circumstance tissue said to possess ‘spare receptors’
33
Q

when is a drug less potent

A

when it requires a higher concentration to elicit 50% maximal response

34
Q

in the presence of a antagonist what happens to concentration-effect curve

A

shifts right, no change in slope or maximum

35
Q

area available for binding

A

1- θ1

36
Q

Rate of diffusion of molecules towards a surface

A
  1. condensation,α

2. Molecules have a rate of diffusion toward a surface (condensation, α)

37
Q

Rate of dissociation away

A
  1. evaporation, V1

2. Molecules have rate of dissociation away from surface (evaporation, V1)

38
Q

rate of adsorption

A

α x µ x (1- θ1)

where µ= drug concentration

39
Q

rate of evaporation

A

V1 x θ1

40
Q

At equilibrium..

A

adsorption = evaporation

41
Q

Equation when at equilibrium

A

θ1 = αµ/(αµ + V1)

42
Q

p

A

fraction of maximal binding

43
Q

[AR]

A

amount of drug receptor complex

44
Q

[R1]

A

total number of receptor sites

45
Q

[A]

A

conc of drug

46
Q

Ka

A

dissociation constant

47
Q

drugs of high potency

A

have high affinity for receptors so have high receptor occupancy even at low concentration

48
Q

where α=

A

intrinsic activity

49
Q

what does this equation assume

A

that relationship between receptor occupancy and tissue response is linear

50
Q

what does our model of receptor-agonist activation suggest

A
  1. Stimulation of receptor leads to response,

2. This implies that the receptor is quiescent and activated only when the agonist molecule is bound

51
Q

constitutive activation

A
  1. Some receptors have a basal level of activation even when no ligand is bound- constitutive activation
  2. Under these conditions, ligands may reduce level of constitutive activation – inverse agonists.
  3. Inverse agonists- can reduce response of agonists but can be blocked by antagonists
52
Q

Inverse agonsits

A

1.ligands that can reduce level of constitutive activation but can be blocked by antagonists

53
Q

Inverse agonists

A
  1. ligands that can reduce level of constitutive activation
54
Q

what can an antagonist do with inverse agonists here

A
  1. only in the presence of agonists/inverse agonists, can restore system towards constitutional level
55
Q

constitutively active receptors

A
  1. higher proportion of receptors occupy R* conformation in the absence of any ligand
56
Q

What is affinity?

A

The property of a molecule being closely associated with a receptor protein.

57
Q

What are some of the forces that control the strength of interaction between a drug and a receptor?

A

Electrostatic, hydrogen bonding, Van der Waals and hydrophobic bonds.

58
Q

What is condensation?

A

The rate of diffusion to a surface.

59
Q

What is evaporation?

A

The rate of dissociation from a surface.

60
Q

What is Ka?

A

The concentration of a drug required to occupy 50% of the total receptor population.

61
Q

What can be used to measure receptor occupancy?

A

Binding experiments.

62
Q

What can Kd values be used for?

A

Compare the affinity of ligands.

63
Q

What is organ selectivity

A
  1. Organ selectivity determined by the biological recognition unit for the drug = receptor.
  2. only acts on an organ if they have receptors for it
64
Q

What is the specificity of a receptor like

A
  1. Specificity is reciprocal
  2. if receptor is only sensitive to a particular transmitter of drug it will only act on those receptors
  3. No drug is completely specific
65
Q

What did James Black do

A
  1. You can take an agonist that produces a response you want to block
  2. Modify its structure
  3. Maintaining or improving affinity
  4. But losing the intrinsic energy
  5. Changing it from agonist to antagonist
  6. He did with histamine -> cimetidine
66
Q

What is an Isotonic transducer

A
  1. measuring tissue which contracts and changes its length
67
Q

What is an Isometric transducer

A
  1. measuring tissue which changes tension
68
Q

How is intrinsic activity measured

A
  1. Maximal response expressed as a fraction of the maximal response for entire system
  2. Full agonist= 1
  3. Full antagonist= 0
69
Q

Describe the Law of mass action

A
  1. At equilibrium KA is a concentration and quantifies affinity
  2. If [A]= KA, then p= 0.5 ( 50% of the total receptor population are bound)
  3. KA is the concentration of the drug required to occupy 50% of the total receptor population
  4. Smaller KA = higher affinity
  5. [R] is free receptor concentration not total receptor concentration. [R]= [RTOT]-[AR]
70
Q

What did Ariens introduce

A
  1. Ariens introduced proportionality factor (α,intrinsic activity) to the binding function
  2. Response= [A]α/[A] + Ka
71
Q

What is receptor reserve

A
  1. Is a property of tissue and agonist (not property of tissue alone)
  2. The magnitude of receptor reserve is very much dependent on the efficacy of the agonist

PA10315 COPY (48 decks)

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