Receptor theory 2

Question 1

Define Intrinsic activity (efficacy) (α)

Answer 1

1. Maximal response expressed as a fraction of the maximal response for the entire system (full agonist = 1, full antagonist = 0)

Question 2

Describe receptor-drug interactions

Answer 2

1. Strength of interaction between a drug and receptor defined by the drug’s affinity for that receptor.
2. Forces controlling affinity are thermodynamic
3. Result: drug resides within a protein binding pocket in a position of minimal free energy.
4. Chemical forces vary according to the distance between drug and receptor binding surface.
5. Drug molecules are not static, but approach and dissociate from the protein surface.
6. Affinity can be modelled by a simple mathematical equation.

Question 3

What are some chemical forces that affect affinity of drug-receptor

Answer 3

1. Electrostatic
2. Hydrogen bonding
3. Van der Waals forces
4. Hydrophobic bonds

Question 4

What was Clarks Quantitative Receptor concept

Answer 4

1. Originator of quantitative receptor theory developed by applying chemical laws to biological phenomena.
2. Suggested that measurable drug-evoked responses in tissues resulted from the unimolecular interaction of the drug and a substance on the cell surface. (1:1 interaction)
3. it is significant that the quantitative relations between the concentration of acetylcholine and its action on smooth muscle cells, could be most accurately expressed by the formulae devised by Langmuir to express the adsorption of gases on metal filaments

Question 5

What is The basics of Langmuir Adsorption Isotherm

Answer 5

1. Total area available for binding = 1
2. Area already bound = θ1
3. Area available for binding = 1 - θ1
4. Molecules have a rate of diffusion toward a surface (condensation, α). – not same alpha as earlier
5. Molecules have a rate of dissociation away from a surface (evaporation, V1).

Question 6

What was Languir equation for rate of adsorption and rate of evaporation

Answer 6

1. Rate of adsorption = α.μ.(1 - θ1)
2. μ = drug concentration
3. Rate of evaporation = V1. θ1

Question 7

What is Langmuir Adsorption Isotherm at equilibrium

Answer 7

1. . At equilibrium, adsorption = evaporation.
   2 . Therefore, α.μ.(1 - θ1) = V1. θ1
2. Re-arrange, θ1 = α.μ./(α.μ. + V1)

Question 8

How can the Langmuir Adsorption Isotherm be re-written in pharmacological nomenclature:

Answer 8

1. ρ =fraction of maximal binding (between 0-1)
2. [AR] =amount of drug-receptor complex
3. [Rt] =total number of receptor sites
4. [A] = concentration of drug
5. KA = dissociation constant
6. p=[AR]/[Rt]=[A]/[A]+KA

Question 9

Describe agonist receptor interaction

Answer 9

1. Agonist and receptors form drug receptors complex
2. Stimulus causes response

Question 10

What is rate of offset/rate of onset

Answer 10

1. Rate of offset/rate of onset = k2/k1= rate of evaporation/condensation

Question 11

What is law of mass action

Answer 11

1. The Law of Mass Action (the rate of reaction is proportional to the product of the concentrations of the reactants) can be applied.
2. At equilibrium the forward and reverse rates are equal.

Question 12

How can k1[A][R]=k2[AR] be rearranged given the law of mass action

Answer 12

1. ([A][R])/[AR]=k2/k1=Ka

Question 13

What does it mean when [A] = KA

Answer 13

1. KA is a concentration and quantifies affinity.
2. If [A] = KA then ρ = 0.5 (i.e. 50% of the total receptor population are bound).
3. Assume [drug] and KA are both 10μmol/L
4. Thus ρ = 10/(10+10) = 10/20 = 0.5
5. KA is therefore the concentration of drug required to occupy 50% of the total receptor population.

Question 14

What does a smaller KA mean

Answer 14

1. The smaller the KA, the higher the affinity.

Answer 15

7. For drug-receptor interactions the Dissociation constant is KA NOT KD which is obtained from ligand binding studies. ???

Question 16

What is [R]

Answer 16

1. Note that [R] is the free receptor concentration; - difference between total number receptors available and those in DR complex
2. [R] = [RTOT]-[DR]

Question 17

What does the Law of Mass Action not give an indication about

Answer 17

1. The binding of a ligand [A] to a receptor R is assumed to follow the Law of Mass Action according to the Langmuir Adsorption Isotherm as defined by Clark (1933).
2. Makes no provision for differing propensities to stimulate receptors. – doesn’t give indication as to what causes different efficacies

Question 18

What did Ariens introduce to the binding function

Answer 18

1. Ariens (1954) introduced the proportionality factor (α, intrinsic activity) to the binding function;
2. Assumes response is a linear function of receptor occupancy multiplied by a constant – the relationship between receptor occupancy and tissue response is non-linear (hyperbolic).

Question 19

What did Stephenson add to the equation

Answer 19

1. Stephenson (1956) introduced the abstract concept of stimulus to the binding function which is the degree of activation given to the receptor upon agonist binding.
2. Magnitude of the stimulus is a function (f) of another abstract quantity called efficacy (e).
3. Efficacy is specific to tissue used and the agonist examined

Question 20

What did Furchgott do

Answer 20

1. Furchgott (1972) redefined the response function in terms of intrinsic efficacy (ε).
2. The product of receptor number ([Rt]) and intrinsic efficacy is the agonist and tissue - dependent element of agonism.

Question 21

Describe receptor occupancy of responses of GPI to histamine

Answer 21

1. Responses of GPI to histamine.
2. Direct correlation between occupancy and response
3. Hyperbolic relation between occupancy and response, according to
4. Response = [A]alpha/[A]+Ka

Question 22

If maximal response is achieved at a concentration where receptor occupancy is about 4% what does that mean

Answer 22

1. Thus about 96% of receptors are not required for a maximal (receptor reserve, ‘spare’ receptors). – agonist only needs to occupy small proportion of receptors to get maximal response

Question 23

What is the receptor reserve

Answer 23

1. A property of the tissue and the agonist (receptor reserve is not a property of the tissue alone). – depends on drug using
2. The magnitude of receptor reserve is very much dependent on the efficacy of the agonist.
3. About spare receptors: This refers to the condition in a tissue whereby the agonist needs to activate only a small fraction of the existing receptor population to produce the maximal system response.
4. Partial agonists may only produce a sub-maximal response even though receptor occupancy is 100%.

Question 24

What is constitutive activation

Answer 24

1. Our model of agonist receptor activation requires stimulation of the receptor that evokes the observed response.
2. This implies that the receptor is quiescent and activated only when the agonist molecule is bound.
3. However, some receptors (benzodiazepines, cannabinoids, dopamine) have a basal level of activation even when no ligand is bound – called constitutive activation.
4. Under these conditions, ligands may reduce the level of constitutive activation – known as inverse agonists.

Question 25

What is difference between inverse agonists and anatagonist

Answer 25

1. Inverse agonists binds, causes stimulus and causes conformational change, reducing response
2. Antagonists bind to receptor but don’t cause stimulus. – can reverse reduced response by inverse agonist
3. Inverse agonist causes reduction in response,
4. in presence of antagonist get rightward shift

Question 26

What is response when increasing does of antagonist to agonist and inverse agonist

Answer 26

1. Standard dose of agonist- Diminish response when adding antagonist
2. Inverse agonist- Increasing antagonist concentration diminishes response of inv agonist to reduce response

Question 27

What is the two-state model receptor activation

Answer 27

1. State of equilibrium between resting and activated state
2. Agonist binds to activated state
3. Fewer receptors in resting state
4. More in activated unbound state
5. Drives system to right to activated state
6. Inverse agonist has preference for resting state
7. Drives system to left- reducing activated state
8. Antagonists blocks both