Effects of agonists

Agonist
Formation of second messengers

Y

effect

cell

• •

Agonists activate receptor, cause a change in intracellular biochemistry and a change in cellular effects
– e.g. formation of second messenger, firing rate of cell, etc

These responses can be measured in a membrane or cellular assay, a tissue bath, an animal or a human to characterize the effects of agonists
– Graded responses: continuous and gradual: measure magnitude of response – Quantal responses: all or nothing: measure frequency of response

To characterize ligands pharmacologically, apply increasing concentrations or administer increasing doses then

Dose-response curve to agonist A
100

RESPONSE (% of maximum)

Dose of A (mg) 0 0.01 0.05 0.1 0.5 1 5 10 50 100 500 1000 5000

Response (HR)

70 70 70 75 85 100 115 125 130 130 130

Respon se (% of maxima l) 0 0 0 8.3 25 50 75 92 100 100 100

80 60

40 20 0 -20 -40

0 60

10 70

20

30

40

50

DOSE (mg) (linear scale)

Dose-response curve to agonist A
(graded response) 100
RESPONSE (% of maximum)
80 60
Dose of A (mg) 0 0.01 0.05 0.1 0.5 1 5 10 50 100 500 1000 5000 Response (HR) 70 70 70 75 85 100 115 125 130 130 130 Respon se (% of maxima l) 0 0 0 8.3 25 50 75 92 100 100 100

40 20 0 -20 -40

0 1000

0.01 10000

0.1

1.0

10

100

DOSE (mg) (log scale)

Dose-response curves
(or concentration-response curves) • The plateau of the curve shows the maximal effect or “Emax” of the drug in the system – A measure of efficacy or effectiveness of the drug – Magnitude of response increases with increasing dose as more agonist-receptor complexes formed The position of the curve along the x-axis shows the potency of the drug – potency is the amount of drug needed to produce an effect – measured as the dose that produces 50% of the maximal response, or, the dose that produces a certain response in 50% of subjects – called “ED50”, the median effective dose (or EC50, the median effective concentration
• The lower the ED50, the more potent is the ligand

– Potency is largely related to the affinity of the agonist for the receptor Efficacy and potency are unrelated. Clinically, efficacy is more important

Dose-response curve to agonist A
(graded Emax 100 response)
RESPONSE (% of maximum)
80 60
Dose of A (mg) 0 0.01 0.05 0.1 0.5 1 5 10 50 100 500 1000 5000 Response (HR) 70 70 70 75 85 100 115 125 130 130 130 Respon se (% of maxima l) 0 0 0 8.3 25 50 75 92 100 100 100

1/2max
response

50
40 20 0 -20 -40

0 1000

0.01 10000

0.1

1.0

10

100

DOSE (mg) (log scale)

ED50 = 1mg

Dose-response curves to agonists A, B, C (graded resonse)
100
Dose (mg) 0 0.01 0.05 0.1 0.5 1 5 10 50 100 500 1000 5000 Response to A (% of maximal) 0 0 0 8.3 25 50 75 92 100 100 100 Response to B (% of maximal) 0 8.3 25 50 75 92 100 100 100 Respons e to C (% of maxima l) 0 0 8.3 21 33 40 40 40

RESPONSE (% of maximum)

80 60

40 20 0 -20 -40

0 1000

0.01 10000

0.1

1.0

10

100

DOSE (mg) (log scale)

Dose-response curve to agonist D
200 subjects tested for therapeutic response

(quantal response) 100
80

Responde rs 0 0 0 16 34 50 50 34 16

RESPONSE (% of total)

Dose of D (mg) 0 0.01 0.05 0.1 0.5 1 5 10 50

Cumulati ve Responde rs 0 0 0 16 50 100 150 184 200

Cumulati ve Responde rs (% of 0 total) 0 0 8 25 50 75 92 100

60

40 20 0 -20 -40

0 1000

0.01 10000

0.1

1.0

10

100

DOSE (mg) (log scale)

Therapeutic and adverse effects of agonist D
(200 subjects)
Dose of D (mg) 0 0.01 0.05 0.1 0.5 1 5 10 50 100 500 1000 5000 1000 0 Therapeu tic responde rs 0 0 0 16 34 50 50 34 16 Cumulati ve therapeut ic responde rs 0 0 0 16 50 100 150 184 200 Cumulati ve therapeut ic responde rs (% of 0 total) 0 0 8 25 50 75 92 100 Number of subjects reporting a certain adverse effect 0 0 0 0 0 0 12 28 48 46 42 18 6 Cumulati ve adverse responde rs 0 0 0 0 0 0 12 40 88 134 176 194 200 Cumulati ve adverse responde rs (% of total) 0 0 0 0 0 0 6 20 44 67 88 97 100 Death s Cumulati ve deaths 0 0 0 0 0 0 0 0 14 44 94 142 191 200 Cumulative deaths (% of total) 0 0 0 0 0 0 0 0 7 22 47 71 95 100

0 0 0 0 0 0 0 0 14 30 50 48 49 9

Dose-response curves for various responses to agonist D
100

RESPONSE (% of total)

Therapeutic effect Adverse effect Lethality Therapeutic Index (TI): = TD50/ED50

80 60

40 20 0

-20 -40

0

0.01 10000

0.1

1.0

10

100

1000

DOSE (mg) (log scale)

Therapeutic Index: a measure of drug safety

Dose-response curves to agonist A and ligands E and F
100
Dose (mg) 0 0.01 0.05 0.1 0.5 1 5 10 50 100 500 1000 5000 Response to A (% of maximal) 0 0 0 8.3 25 50 75 92 100 100 100 Response to E (% of maximal) 0 0 0 0 -5 -12 -25 -30 -30 -30 Respons e to F (% of maxima l) 0 0 0 0 0 0 0 0 0 0

RESPONSE (% of maximum)

80 60

40 20 0 -20 -40

0 1000

0.01 10000

0.1

1.0

10

100

DOSE (mg) (log scale)

Dose-response curves to a full agonist, partial agonist, inverse agonist and neutral antagonist or inactive compound

Neutral antagonist (or an inactive compound)

Textbook figure 1-6

Effect of various doses of antagonist F (inverse agonist or neutral antagonist) on the response to 5 mg dose of agonist A
100
5 mg agonist A after pretreatme nt with various doses of F (mg) 0 0.1 0.5 1 5 10 50 100 500 1000

Response (% of maximal)
75 75 75 75 75 75 65 48 16 0

RESPONSE (% of maximum)

80 60

40 20 0 -20 -40

0 1000

0.01 10000

0.1

1.0

10

100

DOSE of F (mg) (log scale)

Effect of pretreatment with three different fixed doses of antagonist G on the response to agonist B
RESPONSE (% of maximum)
D ose of B (mg ) 0 0.01 0.05 0.1 0.5 1 5 10 50 100 500 1 000 5 000 Respon se to B alone 0 8.3 25 50 75 92 100 100 100 Respon se to B + 1 mg G 0 0 0 18 40 68 84 96 100 Respons e to B + 3 mg G 0 0 0 0 0 12 35 59 81 92 100 Respons e to B + 10 mg G 0 0 0 0 0 0 0 0 10 37 68 89 100

100

80 60

40 20 0 -20 -40

0 1000

0.01 10000

0.1

1.0

10

100

DOSE (mg) (log scale)

Effect of competitive or noncompetitive antagonists on agonist activity

•Parallel rightward shift of D-R curves •Apparent increase in EC50 •Agonist appears less potent in presence of competitive antagonist •No reduction in Emax •Surmountable antagonism •Pharmacological antagonism

•Non-competitive antagonist reduces Emax

Effect of allosteric ligands on agonist activity

Partial agonists can also reduce the response of a full agonist