Pharmacodynamics 2

2019
 Effectmax [Drug]
Effect =
EC50 + [Drug]

koff/kon = KD koff/kon = KD

Aton
At At
Aton

At: antagonist
A: agonist

2
Dose Ratio (DR)
In the absence of antagonist, At: Effect 1 = Effectmax [A]
EC50 +[A]

In the presence of antagonist, At: Effect 2 = Effectmax[At]

EC50 (1+[A]/KA)+[At]

It can be shown that the Dose Ratio is:

agonist concentration (dose) required to produce

a given response (effect) in the presence of an
antagonist Effect 2
DR = =
agonist concentration (dose) required Effect 1
to produce the same response (effect) in the
absence of antagonist

3
 At the equilibrium Effect1 = Effect2, and [A] = [At]:

Effect 1 = Effectmax[At] Effect 2 = Effectmax [A]

EC50 +[A]
EC50 (1+[A]/KA)+[At]

Effect 2 EC50 (1+[A]/KA)+[At] Effectmax [A]

DR = = x
Effect 1 Effectmax[At] EC50 +[A]

DR = 1+[A]/KA
How do we measure KC if it does not directly produce an effect?

We measure KC by analyzing its capacity to compete with and thus reduce the effect
of an agonist.

Agonist A plus increasing concentrations

of competitive antagonist C
Dose Ratio (dr)
120
agonist concentration (dose) required
% of maximal effect

100 to produce a given response (effect)

in the presence of an antagonist
80
agonist concentration (dose) required
60 0.5 Effectmax to produce the same response
(effect) in the absence of antagonist
40

20

-10 -9 -8 -7 -6 -5 -4 -3 -2
Log Agonist

5
 Effectmax [Drug]
Effect =
EC50 + [Drug]

kAToff/kATon = KD kAoff/kAon = KD

ATon
AT T
ATon

C: antagonist
A: agonist

6
 Agonist
• Full Agonists: Compounds that are able to elicit a
maximal response following receptor occupation and
activation.

• Partial Agonists: Compounds that can activate

receptors but are unable to elicit the maximal response
of the receptor system.

• Inverse agonist: an agent which binds to the same

receptor binding-site as an agonist for that receptor and
reverses constitutive activity of receptors. Inverse
agonists exert the opposite pharmacological effect of a
receptor agonist.
7
Biological view of a Full agonist

A1

A2

A2

Inactive
protein Active
protein

8
 Full agonist

120 Full Agonist A

100
% of maximal effect

80 Full Agonist B

60

40

20

0 -3 -2 -1 -0 1 2 3
Log [Agonist]

Full Agonists: Compounds that are able to elicit a maximal response

following receptor occupation and activation.
binding site and, therefore, form an irreversible complex with the receptor.
9
Biological view of Partial Agonists

10
 Partial Agonists

Full Agonist A Full Agonist A

100
100

80
80

response
response

60
60

Partial
Partial 40 Agonist B
40 Agonist B

20
20

0
0-3 -2 -1 -0 1 2 3 -3 -2 -1 -0 1 2 3
Log [Agonist] Log [Agonist]

Compounds that can activate receptors but are unable to elicit the maximal
response of the receptor system.
11
Biological view of Partial Agonists

Peroxisome proliferator-activated
receptor gamma, also known NR1C3
(nuclear receptor subfamily 1, group
C, member 3) is a type II nuclear
receptor

12
Biological view of Inverse Agonists

13
Biological view of Inverse Agonists

14
 Inverse agonist
negative efficacy

Base line

An agent which binds to the same receptor binding-site as an agonist for that
receptor and reverses constitutive activity of receptors. Inverse agonists exert the
opposite pharmacological effect of a receptor agonist. (negative efficacy)
15
 How can an agonist be “partial”?
The molecular basis of partial agonism is unknown. At least 2 theories have
been proposed:

1) The partial agonist may fit the receptor binding site well but is less able to
promote the receptor conformational change leading to transduction.

2) The receptor may isomerize between 2 states – A (active) and I (inactive).

If the A form has high affinity for the agonist (L), the equilibrium will be
shifted in favour of AL and full activation might be achieved.

If I and A forms of the receptor share similar affinities for L, both AL and IL
will be formed but only AL will produce an effect and the agonists will
appear partial.

IL L+I A+L AL
(inactive) (active)

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 Weak partial agonists are also competitive
antagonists
120
Full Agonist A
100
% of maximal effect

80

60
Partial Agonist B
40

20

-11 -9 -7 -5
Log [Agonist]

Drugs A & B have equal affinities for the receptor but B is a partial agonist
17
 Weak partial agonists are also competitive
antagonists
[A] = 0.26 μM
120 [B] is varied

Full Agonist A
100
% of maximal effect

80 Partial Agonist B

60

40

20

0
-12 -10 -8 -6 -4
Log [B]

Here, [A] is fixed and [B] is varied.

As [B] increases, it displaces A and occupies all receptors.
18
 Weak partial agonists are also competitive
antagonists
100
[A] = 0.26 μM
[B] is varied
80
% of maximal effect

Total response

60 Full Agonist A

40

Partial Agonist B
20

0
-12 -10 -8 -6 -4
Log Agonist

Again, [A] is fixed and [B] is varied.

The responses elicited by A and B are shown and the sum of their responses is also
shown. Because the response to B is less than that to A, saturating B reduces the
overall response of the system.
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 Antagonist

• Non-competitive receptor antagonists bind to

the receptor at sites unrelated to the agonist
binding site. Binding of this antagonist is not
reversible or surmountable by increasing
[agonist].

• Competitive reversibly bind to receptors at the

same binding site as the endogenous ligand or
agonist, but without activating the receptor.

20
Biological view of Competitive & Non-
competitive antagonist

21
Non-competitive antagonist

22
Competitive antagonist

23
Biological view of Competitive & Non-
competitive antagonist

24
Receptor-Effector Coupling the interface
between the cell and its environment
Various mechanisms are known to be involved in the processes
between receptor activation and the cellular response (called
receptor-effector coupling).

• The transduction process between receptor occupancy and drug response

is termed coupling.
• The efficiency of coupling is partly determined by the initial conformational
change in the receptor. Thus the effects of full agonists may be more
efficiently coupled to receptor occupancy than those of partial agonists.
• However, coupling efficiency is also determined by the biochemical events
that transduce receptor occupancy into cellular response.

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Receptor-Effector Coupling

26
 Receptor-Effector Coupling
Agonist binding to a receptor and its binding-induced receptor conformational
change is normally the first of many steps required to produce a pharmacological
effect.

27
Receptor-Effector Coupling

28
Receptor-Effector Coupling

29
 Receptor-Effector Coupling
Increasing concentration of
irreversible inhibitor

100
% of maximal effect

80 A
B
60
0.5 Effectmax C
D
40
E
20

0
-11 -10 -9 -8 -7 -6 -5 -4

EC50 (A) EC50 (B) EC50 (C) EC50 (D,E) = KD

Log [Agonist] M
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