Fundamentals of Medicinal Chemistry

Response

0.0

Agonist s normal response

(antagonist is absent)

Antagonist, ideal case

(agonist is absent)

Concentration agonist

% of the
maximum
response

AX 1 X 2 X 3

0%

Log [agonist]

(b)

Log [agonist]

0%

100%

A

X 1

X 2

X 3

Increasing

concentration

% of the of X

maximum

response

(c)

100%

Concentration of X increasing

(a)

Figure 7.8(a) The effect of an ideal antagonist on the response of a receptor. (b) The effect of

different concentrations of an ideal competitive antagonist X on the dose–response curve for an

agonist A. (c) The effect of different concentrations of non-competitive antagonist on the dose–

response curve of drug A. Key: The A plots are the dose–response curves for the agonist in the

absence of the antgonist X. The X 1 –X 3 plots are the dose–response curves for the agonist A in the

presence of three different concentrations of the antagonist X

same receptor as an agonist but do not cause a response (Figure 7.8(a) ). As the

concentration of the competitive antagonist increases, the response due to

agonist decreases. However, increasing the concentration of the agonist will

reverse this decrease (Figure 7.8(b) ). It is believed that non-competitive antag-

onists bind irreversibly by strong bonds, such as covalent bonds, to allosteric

sites on the receptor. This changes the conformation of the receptor site, which

prevents the binding of the agonist to the receptor. In addition, increasing the

concentration of the agonist does not restore the response of the receptor

(Figure 7.8(c) ).

The ideal starting point for the design of a new antagonist would be the

structure of the receptor. However, it is often difficult to identify the receptor

and also obtain the required structural and stereochemical information. Conse-

quently, although it is not the ideal starting point, many developments start with

the structure and stereochemistry of either the endogenous ligand or any other

known agonists and antagonists for the receptor. Since antagonists exert a

stronger affinity for the receptor than its natural agonist, the binding groups

selected for the new drug are often groups that could form stronger bonds with

146 SELECTED EXAMPLES OF DRUG ACTION AT SOME COMMON TARGET AREAS