Lecture Series 1

Question 0

Agonist

Answer 0

Ligands with affinity and efficacy. Maximal response occurs at <100% receptor occupancy due to spare receptors. Hyperbolic relationship between response and agonist concentration.

Question 1

Affinity

Answer 1

The amount of receptor bound by a given concentration of the drug. K1 is the affinity constant, units m^-1

Question 2

Efficacy

Answer 2

The relationship between how much receptor is occupied by a drug, and the size of the response produced

Question 3

Structure activity series

Answer 3

Experiments to calculate the relative potency of a group of structurally related compounds - aids classification.

Question 4

Competitive antagonist

Answer 4

Ligand with with affinity but no efficacy. Right shifts agonist response curve.

Question 6

EC50

Answer 6

The effective concentration of a drug required to produce 50% of the maximal resposne. Measure of potency. EC50 ≠ half 100% receptor occupancy

Question 7

K1/Ka (affinity constant)

Answer 7

K1=[DR]/[D][R]

The reciprocal of the drug concentration that produces 50% occupancy of receptors - not the EC50!

Question 8

Dose ratio

Answer 8

D2/D1 = 1+Ak2
Independent of k1
The dose of agonist needed when A of antagonist is present divided by the dose needed for the same response with no antagonist is equal to 1 plus the antagonist concentration multiplied by the affinity constant of the antagonist

Question 9

Kdiss

Answer 9

Kdiss=[D][R]/[DR]

Question 10

B/Bmax

Answer 10

= Occupancy of receptor by drug = [D]Ka/[D]Ka+1 = [D]/[D]+Kdiss

Question 11

IC50

Answer 11

The inhibitory concentration of a drug required to inhibit 50% of the maximal response

Question 12

Mechanisms of desensitisation of receptors (3)

Answer 12

1) uncoupling from G protein due to phosphorylation events at receptorm (heterologous or homologous)
2) Sequestration removes receptors from plasma membrane by endocytosis
3) Down-regulation by which the number of receptors available are reduced - longer term

Question 13

Heterologous Desensitisation - Uncoupling (B2 receptor)

Answer 13

Receptor can be uncoupled without actually having been stimulated. Occurs with low ligand concentration. Mechanism:

• Another receptor causes a rise in cAMP, causing an increase in PKA mediated phosphorylation
• If sufficient PKA activated, receptor sites phosphorylated
• Phosphorylation uncouples receptor from G protein

Question 14

Homologous Desensitisation - Uncoupling (B2 receptor)

Answer 14

Only works on agonist occupied receptors - receptor must have been activated for it to be desensitised. Occurs with high ligand concentration.

• After ligand binding, receptor can be phosphorylated by B-adrenoreceptor Kinase (BARK) at C terminus
• Phosphorylation here increases affinity for B-arrestin
• B-arrestin uncouples receptor to G protein

Question 15

Insulin

Answer 15

Hormonal agonist

Question 16

Epidermal Growth Factor

Answer 16

Hormonal agonist

Question 17

Platelet Derived Growth Factor

Answer 17

Hormonal agonist

Question 18

Partial Agonist

Answer 18

Ligand with affinity but less efficacy. At 100% receptor occupancy, response is less than maximal. Acts like a competitive inhibitor when used alongside full agonists - stabilises response (clinical use)